Medicament for treatment of cancer

ABSTRACT

A medicament for the prevention and/or treatment of cancers and the like which comprises as an active ingredient a substance selected from the group consisting of a compound represented by the following general formula (I) and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof:  
                 
wherein A represents hydrogen atom or acetyl group, E represents a 2,5-di-substituted or a 3,5-di-substituted phenyl group, or a monocyclic or a fused polycyclic heteroaryl group which may be substituted, provided that the compound wherein said heteroaryl group is {circle around (1)} a fused polycyclic heteroaryl group wherein the ring which binds directly to —CONH— group in the formula (I) is a benzene ring, {circle around (2)} unsubstituted thiazol-2-yl group, or {circle around (3)} unsubstituted benzothiazol-2-yl group is excluded, ring Z represents an arene which may have one or more substituents in addition to the group represented by formula —O-A wherein A has the same meaning as that defined above and the group represented by formula —CONH-E wherein E has the same meaning as that defined above, or a heteroarene which may have one or more substituents in addition to the group represented by formula —O-A wherein A has the same meaning as that defined above and the group represented by formula —CONH-E wherein E has the same meaning as that defined above.

FIELD OF INVENTION

The present invention relates to a medicament which can terminateproliferation of cancer cells which proliferate randomly, and enablespreventive and/or therapeutic treatment of cancers by inducing apoptosisof immortalized cancer cells.

BACKGROUND ART

N-Phenylsalicylamide derivatives are disclosed as a plant growthinhibitor in the specification of U.S. Pat. No. 4,358,443. Asmedicaments, said derivatives are disclosed as anti-inflammatory agentsin the specification of European Patent No. 0,221,211, Japanese PatentUnexamined Publication (KOKAI) No. (Sho)62-99329, and the specificationof U.S. Pat. No. 6,117,859. Furthermore, they are disclosed as NF-κBinhibitors in the pamphlets of International Publication WO99/65499,International Publication WO02/49632, and International PublicationWO02/076918. N-Phenylsalicylamide derivatives are suggested as ananticancer agent in the pamphlets of International PublicationWO99/65499, International Publication WO02/49632, and InternationalPublication WO02/076918. However, absolutely no data that directlyindicate usefulness of those derivatives as anticancer agents isdisclosed. Moreover, in the pamphlet of International PublicationWO99/65449, only a small number of compounds were tested for inhibitoryactivity against NF-κB, and as for a position of a substituent on theaniline moiety, studies were made on very limited compounds.N-Phenylsalicylamide derivatives are disclosed as an inhibitor againstproduction of cytokines in the pamphlet of International PublicationWO02/051397.

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide anticancer agentshaving superior effectiveness and reduced side effects. The inventors ofthe present invention conducted various studies on anticancer actions ofsalicylamide derivatives which are generally considered to have lowtoxicity. As a result, they found that N-substituted salicylamidederivatives, particularly, N-arylsalicylamide derivatives, have superioractivity to have cancer cells trigger apoptosis, and that, even withinan effective dose ranges, said derivatives have no actions that relateto side effects observed with available anticancer agents such ashepatic disorder, renal disorder, or myerosuppression. The inventorsfurther conducted similar studies on hydroxyaryl derivatives which areanalogous compounds thereof. The present invention was achieved on thebasis of these findings.

The present invention thus provides:

(1) A medicament for the preventive and/or therapeutic treatment of acancer which comprises as an active ingredient a substance selected fromthe group consisting of a compound represented by the following generalformula (I) and a pharmacologically acceptable salt thereof, and ahydrate thereof and a solvate thereof:

wherein A represents hydrogen atom or acetyl group,

-   E represents a 2,5-di-substituted or a 3,5-di-substituted phenyl    group, or a monocyclic or a fused polycyclic heteroaryl group which    may be substituted, provided that the compound wherein said    heteroaryl group is {circle around (1)} a fused polycyclic    heteroaryl group wherein the ring which binds directly to —CONH—    group in the formula {circle around (1)} is a benzene ring, {circle    around (2)} unsubstituted thiazol-2-yl group, or {circle around (3)}    unsubstituted benzothiazol-2-yl group is excluded,-   ring Z represents an arene which may have one or more substituents    in addition to the group represented by formula —O-A wherein A has    the same meaning as that defined above and the group represented by    formula —CONH-E wherein E has the same meaning as that defined    above, or a heteroarene which may have one or more substituents in    addition to the group represented by formula —O-A wherein A has the    same meaning as that defined above and the group represented by    formula —CONH-E wherein E has the same meaning as that defined    above.

Examples of preferred medicaments of the present invention include:

(2) the aforementioned medicament which comprises as an activeingredient a substance selected from the group consisting of thecompound and a pharmacologically acceptable salt thereof, and a hydratethereof and a solvate thereof, wherein A is a hydrogen atom;

(3) the aforementioned medicament which comprises as an activeingredient a substance selected from the group consisting of thecompound and a pharmacologically acceptable salt thereof, and a hydratethereof and a solvate thereof, wherein ring Z is a C₆ to C₁₀ arene whichmay have one or more substituents in addition to the group representedby formula —O-A wherein A has the same meaning as that defined in thegeneral formula (I) and the group represented by formula —CONH-E whereinE has the same meaning as that defined in the general formula (I), or a5 to 10-membered heteroarene which may have one or more substituents inaddition to the group represented by formula —O-A wherein A has the samemeaning as that defined in the general formula (I) and the grouprepresented by formula —CONH-E wherein E has the same meaning as thatdefined in the general formula (I);

(4) the aforementioned medicament which comprises as an activeingredient a substance selected from the group consisting of thecompound and a pharmacologically acceptable salt thereof, and a hydratethereof and a solvate thereof, wherein ring Z is a benzene ring whichmay have one or more substituents in addition to the group representedby formula —O-A wherein A has the same meaning as that defined in thegeneral formula (I) and the group represented by formula —CONH-E whereinE has the same meaning as that defined in the general formula (I), or anaphthalene ring which may have one or more substituents in addition tothe group represented by formula —O-A wherein A has the same meaning asthat defined in the general formula (I) and the group represented byformula —CONH-E wherein E has the same meaning as that defined in thegeneral formula (I);

(5) the aforementioned medicament which comprises as an activeingredient a substance selected from the group consisting of a compoundrepresented by the following general formula (I) and a pharmacologicallyacceptable salt thereof, and a hydrate thereof and a solvate thereof,wherein ring Z is a benzene ring which is substituted with halogenatom(s) in addition to the group represented by formula —O-A wherein Ahas the same meaning as that defined in the general formula (I) and thegroup represented by formula —CONH-E wherein E has the same meaning asthat defined in the general formula (I);

(6) the aforementioned medicament which comprises as an activeingredient a substance selected from the group consisting of thecompound and a pharmacologically acceptable salt thereof, and a hydratethereof and a solvate thereof, wherein ring Z is a naphthalene ringwhich may have one or more substituents in addition to the grouprepresented by formula —O-A wherein A has the same meaning as thatdefined in the general formula (I) and the group represented by formula—CONH-E wherein E has the same meaning as that defined in the generalformula (I);

(7) a medicament having inhibitory activity against NF-κB activationwhich comprises as an active ingredient a substance selected from thegroup consisting of a compound represented by the following generalformula (I) and a pharmacologically acceptable salt thereof, and ahydrate thereof and a solvate thereof, wherein E is a 2,5-di-substitutedphenyl group or a 3,5-di-substituted phenyl group;

(8) the aforementioned medicament which comprises as an activeingredient a substance selected from the group consisting of thecompound and a pharmacologically acceptable salt thereof, and a hydratethereof and a solvate thereof, wherein E is a 2,5-di-substituted phenylgroup wherein at least one of said substituents is trifluoromethylgroup, or a 3,5-di-substituted phenyl group wherein at least one of saidsubstituents is trifluoromethyl group;

(9) the aforementioned medicament which comprises as an activeingredient a substance selected from the group consisting of thecompound and a pharmacologically acceptable salt thereof, and a hydratethereof and a solvate thereof, wherein E is3,5-bis(trifluoromethyl)phenyl group;

(10) the aforementioned medicament which comprises as an activeingredient a substance selected from the group consisting of thecompound and a pharmacologically acceptable salt thereof, and a hydratethereof and a solvate thereof, wherein E is a monocyclic or a fusedpolycyclic heteroaryl group which may be substituted, provided that thecompound wherein said heteroaryl group is {circle around (1)} a fusedpolycyclic heteroaryl group wherein the ring which binds directly to—CONH— group in the formula (I) is a benzene ring, {circle around (2)}unsubstituted thiazol-2-yl group, or {circle around (3)} unsubstitutedbenzothiazol-2-yl group is excluded;

(11) the aforementioned medicament which comprises as an activeingredient a substance selected from the group consisting of thecompound and a pharmacologically acceptable salt thereof, and a hydratethereof and a solvate thereof, wherein E is a 5-membered monocyclicheteroaryl group which may be substituted, provided that the compoundswherein said heteroaryl group is unsubstituted thiazol-2-yl group areexcluded.

From another aspect, the present invention provides use of each of thesubstances for manufacture of the medicament according to theaforementioned (1) to (11). The present invention further provides amethod for preventive and/or therapeutic treatment of cancers in amammal including a human, which comprises the step of administering apreventively and/or therapeutically effective amount of each of theaforementioned substances to a mammal including a human.

BRIEF EXPLANATION OF THE DRAWINGS

FIG. 1 shows an inhibitory activity of the medicament of the presentinvention (Compound No. 4) against the proliferation of cancer cells(B16 melanoma).

FIG. 2 shows an inhibitory activity of the medicament of the presentinvention (Compound No. 4) against the proliferation of cancer cells(HT-1080 fibrosarcoma).

FIG. 3 shows an inhibitory activity of the medicament of the presentinvention (Compound No. 4) against the proliferation of cancer cells(NB-1 neuroblastoma).

FIG. 4 shows an inhibitory activity of the medicament of the presentinvention (Compound No. 4) against the proliferation of cancer cells(HMC-1-8 breast cancer).

FIG. 5 shows an anticancer activity of the medicament of the presentinvention (Compound No. 4) against tumors.

BEST MODE FOR CARRYING OUT THE INVENTION

Reference to the disclosure of the pamphlet of International PublicationWO02/49632 is useful for better understanding of the present invention.The entire disclosure of the aforementioned pamphlet of InternationalPublication WO02/49632 is incorporated by reference in the disclosuresof the present specification.

The terms used in the present specification have the following meanings.

As the halogen atom, any of fluorine atom, chlorine atom, bromine atom,or iodine atom may be used unless otherwise specifically referred to.

Examples of the hydrocarbon group include, for example, an aliphatichydrocarbon group, an aryl group, an arylene group, an aralkyl group, abridged cyclic hydrocarbon group, a spiro cyclic hydrocarbon group, anda terpene hydrocarbon.

Examples of the aliphatic hydrocarbon group include, for example, alkylgroup, alkenyl group, alkynyl group, alkylene group, alkenylene group,alkylidene group and the like which are straight chain or branched chainmonovalent or bivalent acyclic hydrocarbon groups; cycloalkyl group,cycloalkenyl group, cycloalkanedienyl group, cycloalkyl-alkyl group,cycloalkylene group, and cycloalkenylene group, which are saturated orunsaturated monovalent or bivalent alicyclic hydrocarbon groups.

Examples of the alkyl group include, for example, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,isopentyl, 2-methylbutyl, 1-methylbutyl, neopentyl, 1,2-dimethylpropyl,1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl,1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl,1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl,1-ethylbutyl, 1-ethyl-1-methylpropyl, n-heptyl, n-octyl, n-nonyl,n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, andn-pentadecyl, which are C₁ to C₁₅ straight chain or branched chain alkylgroups.

Examples of the alkenyl group include, for example, vinyl,prop-1-en-1-yl, allyl, isopropenyl, but-1-en-1-yl, but-2-en-1-yl,but-3-en-1-yl, 2-methylprop-2-en-1-yl, 1-methylprop-2-en-1-yl,pent-1-en-1-yl, pent-2-en-1-yl, pent-3-en-1-yl, pent-4-en-1-yl,3-methylbut-2-en-1-yl, 3-methylbut-3-en-1-yl, hex-1-en-1-yl,hex-2-en-1-yl, hex-3-en-1-yl, hex-4-en-1-yl, hex-5-en-1-yl,4-methylpent-3-en-1-yl, 4-methylpent-3-en-1-yl, hept-1-en-1-yl,hept-6-en-1-yl, oct-1-en-1-yl, oct-7-en-1-yl, non-1-en-1-yl,non-8-en-1-yl, dec-1-en-1-yl, dec-9-en-1-yl, undec-1-en-1-yl,undec-10-en-1-yl, dodec-1-en-1-yl, dodec-11-en-1-yl, tridec-1-en-1-yl,tridec-12-en-1-yl, tetradec-1-en-1-yl, tetradec-13-en-1-yl,pentadec-1-en-1-yl, and pentadec-14-en-1-yl, which are C₂ to C₁₅straight chain or branched chain alkenyl groups.

Examples of the alkynyl group include, for example, ethynyl,prop-1-yn-1-yl, prop-2-yn-1-yl, but-1-yn-1-yl, but-3-yn-1-yl,1-methylprop-2-yn-1-yl, pent-1-yn-1-yl, pent-4-yn-1-yl, hex-1-yn-1-yl,hex-5-yn-1-yl, hept-1-yn-1-yl, hept-6-yn-1-yl, oct-1-yn-1-yl,oct-7-yn-1-yl, non-1-yn-1-yl, non-8-yn-1-yl, dec-1-yn-1-yl,dec-9-yn-1-yl, undec-1-yn-1-yl, undec-10-yn-1-yl, dodec-1-yn-1-yl,dodec-11-yn-1-yl, tridec-1-yn-1-yl, tridec-12-yn-1-yl,tetradec-1-yn-1-yl, tetradec-13-yn-1-yl, pentadec-1-yn-1-yl, andpentadec-14-yn-1-yl, which are C₂ to C₁₅ straight chain or branchedchain alkynyl groups.

Examples of the alkylene group include, for example, methylene,ethylene, ethane-1,1-diyl, propane-1,3-diyl, propane-1,2-diyl,propane-2,2-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl,and 1,1,4,4-tetramethylbutane-1,4-diyl group, which are C₁ to C₈straight chain or branched chain alkylene groups.

Examples of the alkenylene group include, for example, ethene-1,2-diyl,propene-1,3-diyl, but-1-ene-1,4-diyl, but-2-ene-1,4-diyl,2-methylpropene-1,3-diyl, pent-2-ene-1,5-diyl, and hex-3-ene-1,6-diyl,which are C₁ to C₆ straight chain or branched chain alkylene groups.

Examples of the alkylidene group include, for example, methylidene,ethylidene, propylidene, isopropylidene, butylidene, pentylidene, andhexylidene, which are C₁ to C₆ straight chain or branched chainalkylidene groups.

Examples of the cycloalkyl group include, for example, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, whichare C₃ to C₈ cycloalkyl groups.

The aforementioned cycloalkyl group may be fused with benzene ring,naphthalene ring and the like, and examples include, for example,1-indanyl, 2-indanyl, 1,2,3,4-tetrahydronaphthalen-1-yl, and1,2,3,4-tetrahydronaphthalen-2-yl.

Examples of the cycloalkenyl group include, for example,2-cyclopropen-1-yl, 2-cyclobuten-1-yl, 2-cyclopenten-1-yl,3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl,1-cyclobuten-1-yl, and 1-cyclopenten-1-yl, which are C₃ to C₆cycloalkenyl groups.

The aforementioned cycloalkenyl group may be fused with benzene ring,naphthalene ring and the like, and examples include, for example,1-indanyl, 2-indanyl, 1,2,3,4-tetrahydronaphthalen-1-yl,1,2,3,4-tetrahydronaphthalen-2-yl, 1-indenyl, and 2-indenyl.

Examples of the cycloalkanedienyl group include, for example,2,4-cyclopentadien-1-yl, 2,4-cyclohexanedien-1-yl, and2,5-cyclohexanedien-1-yl, which are C₅ to C₆ cycloalkanedienyl groups.

The aforementioned cycloalkanedienyl group may be fused with benzenering, naphthalene ring and the like, and examples include, for example,1-indenyl and 2-indenyl.

Examples of the cycloalkyl-alkyl group include the groups in which onehydrogen atom of the alkyl group is substituted with a cycloalkyl group,and include, for example, cyclopropylmethyl, 1-cyclopropylethyl,2-cyclopropylethyl, 3-cyclopropylpropyl, 4-cyclopropylbutyl,5-cyclopropylpentyl, 6-cyclopropylhexyl, cyclobutylmethyl,cyclopentylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, cyclohexylpropyl, cyclohexylbutyl, cycloheptylmethyl,cyclooctylmethyl, and 6-cyclooctylhexyl, which are C₄ to C₁₄cycloalkyl-alkyl groups.

Examples of the cycloalkylene group include, for example,cyclopropane-1,1-diyl, cyclopropane-1,2-diyl, cyclobutane-1,1-diyl,cyclobutane-1,2-diyl, cyclobutane-1,3-diyl, cyclopentane-1,1-diyl,cyclopentane-1,2-diyl, cyclopentane-1,3-diyl, cyclohexane-1,1-diyl,cyclohexane-1,2-diyl, cyclohexane-1,3-diyl, cyclohexane-1,4-diyl,cycloheptane-1,1-diyl, cycloheptane-1,2-diyl, cyclooctane-1,1-diyl, andcyclooctane-1,2-diyl, which are C₃ to C₈ cycloalkylene groups.

Examples of the cycloalkenylene group include, for example,2-cyclopropene-1,1-diyl, 2-cyclobutene-1,1-diyl,2-cyclopentene-1,1-diyl, 3-cyclopentene-1,1-diyl,2-cyclohexene-1,1-diyl, 2-cyclohexene-1,2-diyl, 2-cyclohexene-1,4-diyl,3-cyclohexene-1,1-diyl, 1-cyclobutene-1,2-diyl, 1-cyclopentene-1,2-diyl,and 1-cyclohexene-1,2-diyl, which are C₃ to C₆ cycloalkenylene groups.

Examples of the aryl group include a monocyclic or a fused polycyclicaromatic hydrocarbon group, and include, for example, phenyl,1-naphthyl, 2-naphthyl, anthryl, phenanthryl, and acenaphthylenyl, whichare C₆ to C₁₄ aryl groups.

The aforementioned aryl group may be fused with the aforementioned C₃ toC₈ cycloalkyl group, C₃ to C₆ cycloalkenyl group, C₅ to C₆cycloalkanedienyl group or the like, and examples include, for example,4-indanyl, 5-indanyl, 1,2,3,4-tetrahydronaphthalen-5-yl,1,2,3,4-tetrahydronaphthalen-6-yl, 3-acenaphthenyl, 4-acenaphthenyl,inden-4-yl, inden-5-yl, inden-6-yl, inden-7-yl, 4-phenalenyl,5-phenalenyl, 6-phenalenyl, 7-phenalenyl, 8-phenalenyl, and9-phenalenyl.

Examples of the arylene group include, for example, 1,2-phenylene,1,3-phenylene, 1,4-phenylene, naphthalene-1,2-diyl,naphthalene-1,3-diyl, naphthalene-1,4-diyl, naphthalene-1,5-diyl,naphthalene-1,6-diyl, naphthalene-1,7-diyl, naphthalene-1,8-diyl,naphthalene-2,3-diyl, naphthalene-2,4-diyl, naphthalene-2,5-diyl,naphthalene-2,6-diyl, naphthalene-2,7-diyl, naphthalene-2,8-diyl, andanthracene-1,4-diyl, which are C₆ to C₁₄ arylene groups.

Examples of the aralkyl group include the groups in which one hydrogenatom of the alkyl group is substituted with an aryl group, and include,for example, benzyl, 1-naphthylmethyl, 2-naphthylmethyl,anthracenylmethyl, phenanthrenylmethyl, acenaphthylenylmethyl,diphenylmethyl, 1-phenethyl, 2-phenethyl, 1-(1-naphthyl)ethyl,1-(2-naphthyl)ethyl, 2-(1-naphthyl)ethyl, 2-(2-naphthyl)ethyl,3-phenylpropyl, 3-(1-naphthyl)propyl, 3-(2-naphthyl)propyl,4-phenylbutyl, 4-(1-naphthyl)butyl, 4-(2-naphthyl)butyl, 5-phenylpentyl,5-(1-naphthyl)pentyl, 5-(2-naphthyl)pentyl, 6-phenylhexyl,6-(1-naphthyl)hexyl, and 6-(2-naphthyl)hexyl, which are C₇ to C₁₆aralkyl groups.

Examples of the bridged cyclic hydrocarbon group include, for example,bicyclo[2.1.0]pentyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]octyl, andadamantyl.

Examples of the spiro cyclic hydrocarbon group include, for example,spiro[3.4]octyl, and spiro[4.5]deca-1,6-dienyl.

Examples of the terpene hydrocarbon include, for example, geranyl,neryl, linalyl, phytyl, menthyl, and bornyl.

Examples of the halogenated alkyl group include the groups in which onehydrogen atom of the alkyl group is substituted with a halogen atom, andinclude, for example, fluoromethyl, difluoromethyl, trifluoromethyl,chloromethyl, dichloromethyl, trichloromethyl, bromomethyl,dibromomethyl, tribromomethyl, iodomethyl, diiodomethyl, triiodomethyl,2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl,heptafluoropropyl, heptafluoroisopropyl, nonafluorobutyl, andperfluorohexyl, which are C₁ to C₆ straight chain or branched chainhalogenated alkyl groups substituted with 1 to 13 halogen atoms.

Examples of the heterocyclic group include, for example, a monocyclic ora fused polycyclic hetero aryl group which comprises at least one atomof 1 to 3 kinds of hetero atoms selected from oxygen atom, sulfur atom,nitrogen atom and the like as ring-constituting atoms (ring formingatoms), and a monocyclic or a fused polycyclic non-aromatic heterocyclicgroup which comprises at least one atom of 1 to 3 kinds of hetero atomsselected from oxygen atom, sulfur atom, nitrogen atom and the like asring-constituting atoms (ring forming atoms).

Examples of the monocyclic heteroaryl group include, for example,2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 1-pyrrolyl, 2-pyrrolyl,3-pyrrolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1-imidazolyl,2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 1-pyrazolyl, 3-pyrazolyl,4-pyrazolyl, 5-pyrazolyl, (1,2,3-oxadiazol)-4-yl,(1,2,3-oxadiazol)-5-yl, (1,2,4-oxadiazol)-3-yl, (1,2,4-oxadiazol)-5-yl,(1,2,5-oxadiazol)-3-yl, (1,2,5-oxadiazol)-4-yl, (1,3,4-oxadiazol)-2-yl,(1,3,4-oxadiazol)-5-yl, furazanyl, (1,2,3-thiadiazol)-4-yl,(1,2,3-thiadiazol)-5-yl, (1,2,4-thiadiazol)-3-yl,(1,2,4-thiadiazol)-5-yl, (1,2,5-thiadiazol)-3-yl,(1,2,5-thiadiazol)-4-yl, (1,3,4-thiadiazolyl)-2-yl,(1,3,4-thiadiazolyl)-5-yl, (1H-1,2,3-triazol)-1-yl,(1H-1,2,3-triazol)-4-yl, (1H-1,2,3-triazol)-5-yl,(2H-1,2,3-triazol)-2-yl, (2H-1,2,3-triazol)-4-yl,(1H-1,2,4-triazol)-1-yl, (1H-1,2,4-triazol)-3-yl,(1H-1,2,4-triazol)-5-yl, (4H-1,2,4-triazol)-3-yl,(4H-1,2,4-triazol)-4-yl, (1H-tetrazol)-1-yl, (1H-tetrazol)-5-yl,(2H-tetrazol)-2-yl, (2H-tetrazol)-5-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl,3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl, 2-pyrazinyl, (1,2,3-triazin)-4-yl, (1,2,3-triazin)-5-yl,(1,2,4-triazin)-3-yl, (1,2,4-triazin)-5-yl, (1,2,4-triazin)-6-yl,(1,3,5-triazin)-2-yl, 1-azepinyl, 2-azepinyl, 3-azepinyl, 4-azepinyl,(1,4-oxazepin)-2-yl, (1,4-oxazepin)-3-yl, (1,4-oxazepin)-5-yl,(1,4-oxazepin)-6-yl, (1,4-oxazepin)-7-yl, (1,4-thiazepin)-2-yl,(1,4-thiazepin)-3-yl, (1,4-thiazepin)-5-yl, (1,4-thiazepin)-6-yl, and(1,4-thiazepin)-7-yl, which are 5 to 7-membered monocyclic heteroarylgroups.

Examples of the fused polycyclic heteroaryl group include, for example,2-benzofuranyl, 3-benzofuranyl, 4-benzofuranyl, 5-benzofuranyl,6-benzofuranyl, 7-benzofuranyl, 1-isobenzofuranyl, 4-isobenzofuranyl,5-isobenzofuranyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl,4-benzo[b]thienyl, 5-benzo[b]thienyl, 6-benzo[b]thienyl,7-benzo[b]thienyl, 1-benzo[c]thienyl, 4-benzo[c]thienyl,5-benzo[c]thienyl, 1-indolyl, 1-indolyl, 2-indolyl, 3-indolyl,4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, (2H-isoindol)-1-yl,(2H-isoindol)-2-yl, (2H-isoindol)-4-yl, (2H-isoindol)-5-yl,(1H-indazol)-1-yl, (1H-indazol)-3-yl, (1H-indazol)-4-yl,(1H-indazol)-5-yl, (1H-indazol)-6-yl, (1H-indazol)-7-yl,(2H-indazol)-1-yl, (2H-indazol)-2-yl, (2H-indazol)-4-yl,(2H-indazol)-5-yl, 2-benzoxazolyl, 2-benzoxazolyl, 4-benzoxazolyl,5-benzoxazolyl, 6-benzoxazolyl, 7-benzoxazolyl, (1,2-benzisoxazol)-3-yl,(1,2-benzisoxazol)-4-yl, (1,2-benzisoxazol)-5-yl,(1,2-benzisoxazol)-6-yl, (1,2-benzisoxazol)-7-yl,(2,1-benzisoxazol)-3-yl, (2,1-benzisoxazol)-4-yl,(2,1-benzisoxazol)-5-yl, (2,1-benzisoxazol)-6-yl,(2,1-benzisoxazol)-7-yl, 2-benzothiazolyl, 4-benzothiazolyl,5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl,(1,2-benzisothiazol)-3-yl, (1,2-benzisothiazol)-4-yl,(1,2-benzisothiazol)-5-yl, (1,2-benzisothiazol)-6-yl,(1,2-benzisothiazol)-7-yl, (2,1-benzisothiazol)-3-yl,(2,1-benzisothiazol)-4-yl, (2,1-benzisothiazol)-5-yl,(2,1-benzisothiazol)-6-yl, (2,1-benzisothiazol)-7-yl,(1,2,3-benzoxadiazol)-4-yl, (1,2,3-benzoxadiazol)-5-yl,(1,2,3-benzoxadiazol)-6-yl, (1,2,3-benzoxadiazol)-7-yl,(2,1,3-benzoxadiazol)-4-yl, (2,1,3-benzoxadiazol)-5-yl,(1,2,3-benzothiadiazol)-4-yl, (1,2,3-benzothiadiazol)-5-yl,(1,2,3-benzothiadiazol)-6-yl, (1,2,3-benzothiadiazol)-7-yl,(2,1,3-benzothiadiazol)-4-yl, (2,1,3-benzothiadiazol)-5-yl,(1H-benzotriazol)-1-yl, (1H-benzotriazol)-4-yl, (1H-benzotriazol)-5-yl,(1H-benzotriazol)-6-yl, (1H-benzotriazol)-7-yl, (2H-benzotriazol)-2-yl,(2H-benzotriazol)-4-yl, (2H-benzotriazol)-5-yl, 2-quinolyl, 3-quinolyl,4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl,1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl,6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl, 3-cinnolinyl, 4-cinnolinyl,5-cinnolinyl, 6-cinnolinyl, 7-cinnolinyl, 8-cinnolinyl, 2-quinazolinyl,4-quinazolinyl, 5-quinazolinyl, 6-quinazolinyl, 7-quinazolinyl,8-quinazolinyl, 2-quinoxalinyl, 5-quinoxalinyl, 6-quinoxalinyl,1-phthalazinyl, 5-phthalazinyl, 6-phthalazinyl, 2-naphthyridinyl,3-naphthyridinyl, 4-naphthyridinyl, 2-purinyl, 6-purinyl, 7-purinyl,8-purinyl, 2-pteridinyl, 4-pteridinyl, 6-pteridinyl, 7-pteridinyl,1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl, 9-carbazolyl,2-(α-carbolinyl), 3-(α-carbolinyl), 4-(α-carbolinyl), 5-(α-carbolinyl),6-(α-carbolinyl), 7-(α-carbolinyl), 8-(α-carbolinyl), 9-(α-carbolinyl),1-(β-carbolinyl), 3-(β-carbolinyl), 4-(β-carbolinyl), 5-(β-carbolinyl),6-(β-carbolinyl), 7-(β-carbolinyl), 8-(β-carbolinyl), 9-(β-carbolinyl),1-(γ-carbolinyl), 2-(γ-carbolinyl), 4-(γ-carbolinyl), 5-(γ-carbolinyl),6-(γ-carbolinyl), 7-(γ-carbolinyl), 8-(γ-carbolinyl), 9-(γ-carbolinyl),1-acridinyl, 2-acridinyl, 3-acridinyl, 4-acridinyl, 9-acridinyl,1-phenoxazinyl, 2-phenoxazinyl, 3-phenoxazinyl, 4-phenoxazinyl,10-phenoxazinyl, 1-phenothiazinyl, 2-phenothiazinyl, 3-phenothiazinyl,4-phenothiazinyl, 10-phenothiazinyl, 1-phenazinyl, 2-phenazinyl,1-phenanthridinyl, 2-phenanthridinyl, 3-phenanthridinyl,4-phenanthridinyl, 6-phenanthridinyl, 7-phenanthridinyl,8-phenanthridinyl, 9-phenanthridinyl, 10-phenanthridinyl,2-phenanthrolinyl, 3-phenanthrolinyl, 4-phenanthrolinyl,5-phenanthrolinyl, 6-phenanthrolinyl, 7-phenanthrolinyl,8-phenanthrolinyl, 9-phenanthrolinyl, 10-phenanthrolinyl,1-thianthrenyl, 2-thianthrenyl, 1-indolizinyl, 2-indolizinyl,3-indolizinyl, 5-indolizinyl, 6-indolizinyl, 7-indolizinyl,8-indolizinyl, 1-phenoxathiinyl, 2-phenoxathiinyl, 3-phenoxathiinyl,4-phenoxathiinyl, thieno[2,3-b]furyl, pyrrolo[1,2-b]pyridazinyl,pyrazolo[1,5-a]pyridyl, imidazo[11,2-a]pyridyl, imidazo[1,5-a]pyridyl,imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl,1,2,4-triazolo[4,3-a]pyridyl, and 1,2,4-triazolo[4,3-a]pyridazinyl,which are 8 to 14-membered fused polycyclic heteroaryl groups.

Examples of the monocyclic non-aromatic heterocyclic group include, forexample, 1-aziridinyl, 1-azetidinyl, 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, 2-tetrahydrofuryl, 3-tetrahydrofuryl, thiolanyl,1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 1-pyrazolidinyl,3-pyrazolidinyl, 4-pyrazolidinyl, 1-(2-pyrrolinyl), 1-(2-imidazolinyl),2-(2-imidazolinyl), 1-(2-pyrazolinyl), 3-(2-pyrazolinyl), piperidino,2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-homopiperidinyl,2-tetrahydropyranyl, morpholino, (thiomorpholin)-4-yl, 1-piperazinyl,and 1-homopiperazinyl, which are 3 to 7-membered saturated orunsaturated monocyclic non-aromatic heterocyclic groups.

Examples of the fused polycyclic non-aromatic heterocyclic groupinclude, for example, 2-quinuclidinyl, 2-chromanyl, 3-chromanyl,4-chromanyl, 5-chromanyl, 6-chromanyl, 7-chromanyl, 8-chromanyl,1-isochromanyl, 3-isochromanyl, 4-isochromanyl, 5-isochromanyl,6-isochromanyl, 7-isochromanyl, 8-isochromanyl, 2-thiochromanyl,3-thiochromanyl, 4-thiochromanyl, 5-thiochromanyl, 6-thiochromanyl,7-thiochromanyl, 8-thiochromanyl, 1-isothiochromanyl,3-isothiochromanyl, 4-isothiochromanyl, 5-isothiochromanyl,6-isothiochromanyl, 7-isothiochromanyl, 8-isothiochromanyl, 1-indolinyl,2-indolinyl, 3-indolinyl, 4-indolinyl, 5-indolinyl, 6-indolinyl,7-indolinyl, 1-isoindolinyl, 2-isoindolinyl, 4-isoindolinyl,5-isoindolinyl, 2-(4H-chromenyl), 3-(4H-chromenyl), 4-(4H-chromenyl),5-(4H-chromenyl), 6-(4H-chromenyl), 7-(4H-chromenyl), 8-(4H-chromenyl),1-isochromenyl, 3-isochromenyl, 4-isochromenyl, 5-isochromenyl,6-isochromenyl, 7-isochromenyl, 8-isochromenyl, 1-(1H-pyrrolidinyl),2-(1H-pyrrolidinyl), 3-(1H-pyrrolidinyl), 5-(1H-pyrrolidinyl),6-(1H-pyrrolidinyl), and 7-(1H-pyrrolidinyl), which are 8 to 10-memberedsaturated or unsaturated fused polycyclic non-aromatic heterocyclicgroups.

Among the aforementioned heterocyclic groups, a monocyclic or a fusedpolycyclic hetero aryl groups which may have 1 to 3 kinds of heteroatoms selected from oxygen atom, sulfur atom, nitrogen atom and thelike, in addition to the nitrogen atom that has the bond, asring-constituting atoms (ring forming atoms), and a monocyclic or afused polycyclic non-aromatic heterocyclic groups which may have 1 to 3kinds of hetero atoms selected from oxygen atom, sulfur atom, nitrogenatom and the like, in addition to the nitrogen atom that has the bond,as ring-constituting atoms (ring forming atoms) are referred to as“cyclic amino group.” Examples include, for example, 1-pyrrolidinyl,1-imidazolidinyl, 1-pyrazolidinyl, 1-oxazolidinyl, 1-thiazolidinyl,piperidino, morpholino, 1-piperazinyl, thiomorpholin-4-yl,1-homopiperidinyl, 1-homopiperazinyl, 2-pyrolin-1-yl, 2-imidazolin-1-yl,2-pyrazolin-1-yl, 1-indolinyl, 2-isoindolinyl,1,2,3,4-tetrahydroquinolin-1-yl, 1,2,3,4-tetrahydroisoquinolin-2-yl,1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, 1-indolyl, 1-indazolyl, and2-isoindolyl.

The aforementioned cycloalkyl group, cycloalkenyl group,cycloalkanedienyl group, aryl group, cycloalkylene group,cycloalkenylene group, arylene group, bridged cyclic hydrocarbon group,spiro cyclic hydrocarbon group, and heterocyclic group are genericallyreferred to as “cyclic group.” Furthermore, among said cyclic groups,particularly, aryl group, arylene group, monocyclic heteroaryl group,and fused polycyclic heteroaryl group are generically referred to as“aromatic ring group.” Examples of the hydrocarbon-oxy group include thegroups in which a hydrogen atom of the hydroxy group is substituted witha hydrocarbon group, and examples of the hydrocarbon include similargroups to the aforementioned hydrocarbon groups. Examples of thehydrocarbon-oxy group include, for example, alkoxy group (alkyl-oxygroup), alkenyl-oxy group, alkynyl-oxy group, cycloalkyl-oxy group,cycloalkyl-alkyl-oxy group and the like, which are aliphatichydrocarbon-oxy groups; aryl-oxy group; aralkyl-oxy group; andalkylene-dioxy group.

Examples of the alkoxy (alkyl-oxy group) include, for example, methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy,tert-butoxy, n-pentyloxy, isopentyloxy, 2-methylbutoxy, 1-methylbutoxy,neopentyloxy, 1,2-dimethylpropoxy, 1-ethylpropoxy, n-hexyloxy,4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy,1-methylpentyloxy, 3,3-dimethylbutoxy, 2,2-dimethybutoxy,1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy,2,3-dimethylbutoxy, 2-ethylbutoxy, 1-ethylbutoxy,1-ethyl-1-methylpropoxy, n-heptyloxy, n-octyloxy, n-nonyloxy,n-decyloxy, n-undecyloxy, n-dodecyloxy, n-tridecyloxy, n-tetradecyloxy,and n-pentadecyloxy, which are C₁ to C₁₅ straight chain or branchedchain alkoxy groups.

Examples of the alkenyl-oxy group include, for example, vinyloxy,(prop-1-en-1-yl)oxy, allyloxy, isopropenyloxy, (but-1-en-1-yl)oxy,(but-2-en-1-yl)oxy, (but-3-en-1-yl)oxy, (2-methylprop-2-en-1-yl)oxy,(1-methylprop-2-en-1-yl)oxy, (pent-1-en-1-yl)oxy, (pent-2-en-1-yl)oxy,(pent-3-en-1-yl)oxy, (pent-4-en-1-yl)oxy, (3-methylbut-2-en-1-yl)oxy,(3-methylbut-3-en-1-yl)oxy, (hex-1-en-1-yl)oxy, (hex-2-en-1-yl)oxy,(hex-3-en-1-yl)oxy, (hex-4-en-1-yl)oxy, (hex-5-en-1-yl)oxy,(4-methylpent-3-en-1-yl)oxy, (4-methylpent-3-en-1-yl)oxy,(hept-1-en-1-yl)oxy, (hept-6-en-1-yl)oxy, (oct-1-en-1-yl)oxy,(oct-7-en-1-yl)oxy, (non-1-en-1-yl)oxy, (non-8-en-1-yl)oxy,(dec-1-en-1-yl)oxy, (dec-9-en-1-yl)oxy, (undec-1-en-1-yl)oxy,(undec-10-en-1-yl)oxy, (dodec-1-en-1-yl)oxy, (dodec-11-en-1-yl)oxy,(tridec-1-en-1-yl)oxy, (tridec-12-en-1-yl)oxy, (tetradec-1-en-1-yl)oxy,(tetradec-13-en-1-yl)oxy, (pentadec-1-en-1-yl)oxy, and(pentadec-14-en-1-yl)oxy, which are C₂ to C₁₅ straight chain or branchedchain alkenyl-oxy groups.

Examples of the alkynyl-oxy group include, for example, ethynyloxy,(prop-1-yn-1-yl)oxy, (prop-2-yn-1-yl)oxy, (but-1-yn-1-yl)oxy,(but-3-yn-1-yl)oxy, (1-methylprop-2-yn-1-yl)oxy, (pent-1-yn-1-yl)oxy,(pent-4-yn-1-yl)oxy, (hex-1-yn-1-yl)oxy, (hex-5-yn-1-yl)oxy,(hept-1-yn-1-yl)oxy, (hept-6-yn-1-yl)oxy, (oct-1-yn-1-yl)oxy,(oct-7-yn-1-yl)oxy, (non-1-yn-1-yl)oxy, (non-8-yn-1-yl)oxy,(dec-1-yn-1-yl)oxy, (dec-9-yn-1-yl)oxy, (undec-1-yn-1-yl)oxy,(undec-10-yn-1-yl)oxy, (dodec-1-yn-1-yl)oxy, (dodec-11-yn-1-yl)oxy,(tridec-1-yn-1-yl)oxy, (tridec-12-yn-1-yl)oxy, (tetradec-1-yn-1-yl)oxy,(tetradec-13-yn-1-yl)oxy, (pentadec-1-yn-1-yl)oxy, and(pentadec-14-yn-1-yl)oxy, which are C₂ to C₁₅ straight chain or branchedchain alkynyl-oxy groups.

Examples of the cycloalkyl-oxy group include, for example, cyclopropoxy,cyclobutoxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, andcyclooctyloxy, which are C₃ to C₈ cycloalkyl-oxy groups.

Examples of the cycloalkyl-alkyl-oxy group include, for example,cyclopropylmethoxy, 1-cyclopropylethoxy, 2-cyclopropylethoxy,3-cyclopropylpropoxy, 4-cyclopropylbutoxy, 5-cyclopropylpentyloxy,6-cyclopropylhexyloxy, cyclobutylmethoxy, cyclopentylmethoxy,cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy,2-cyclohexylethoxy, 3-cyclohexylpropoxy, 4-cyclohexylbutoxy,cycloheptylmethoxy, cyclooctylmethoxy, and 6-cyclooctylhexyloxy, whichare C₄ to C₁₄ cycloalkyl-alkyl-oxy groups.

Examples of the aryl-oxy group include, for example, phenoxy,1-naphthyloxy, 2-naphthyloxy, anthryloxy, phenanthryloxy, andacenaphthylenyloxy, which are C₆ to C₁₄ aryl-oxy groups.

Examples of the aralkyl-oxy group include, for example, benzyloxy,1-naphthylmethoxy, 2-naphthylmethoxy, anthracenylmethoxy,phenanthrenylmethoxy, acenaphthylenylmethoxy, diphenylmethoxy,1-phenethyloxy, 2-phenethyloxy, 1-(1-naphthyl)ethoxy,1-(2-naphthyl)ethoxy, 2-(1-naphthyl)ethoxy, 2-(2-naphthyl)ethoxy,3-phenylpropoxy, 3-(1-naphthyl)propoxy, 3-(2-naphthyl)propoxy,4-phenylbutoxy, 4-(1-naphthyl)butoxy, 4-(2-naphthyl)butoxy,5-phenylpentyloxy, 5-(1-naphthyl)pentyloxy, 5-(2-naphthyl)pentyloxy,6-phenylhexyloxy, 6-(1-naphthyl)hexyloxy, and 6-(2-naphthyl)hexyloxy,which are C₇ to C₁₆ aralkyl-oxy groups.

Examples of the alkylenedioxy group include, for example,methylenedioxy, ethylenedioxy, 1-methylmethylenedioxy, and1,1-dimethylmethylenedioxy.

Examples of the halogenated alkoxy group (halogenated alkyl-oxy group)include the groups in which a hydrogen atom of the hydroxy group issubstituted with a halogenated alkyl group, and include, for example,fluoromethoxy, difluoromethoxy, chloromethoxy, bromomethoxy,iodomethoxy, trifluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy,pentafluoroethoxy, 3,3,3-trifluoropropoxy, heptafluoropropoxy,heptafluoroisopropoxy, nonafluorobutoxy, and perfluorohexyloxy, whichare C₁ to C₆ straight chain or branched chain halogenated alkoxy groupssubstituted with 1 to 13 halogen atoms.

Examples of the heterocyclic-oxy group include the groups in which ahydrogen atom of the hydroxy group is substituted with a heterocyclicgroup, and examples of the heterocyclic ring include similar groups tothe aforementioned heterocyclic groups. Examples of the heterocyclic-oxygroup include, for example, a monocyclic heteroaryl-oxy group, a fusedpolycyclic heteroaryl-oxy group, a monocyclic non-aromaticheterocyclic-oxy group, and a fused polycyclic non-aromaticheterocyclic-oxy group.

Examples of the monocyclic heteroaryl-oxy group include, for example,3-thienyloxy, (isoxazol-3-yl)oxy, (thiazol-4-yl)oxy, 2-pyridyloxy,3-pyridyloxy, 4-pyridyloxy, and (pyrimidin-4-yl)oxy.

Examples of the fused polycyclic heteroaryl-oxy group include, forexample, 5-indolyloxy, (benzimidazol-2-yl)oxy, 2-quinolyloxy,3-quinolyloxy, and 4-quinolyloxy.

Examples of the monocyclic non-aromatic heterocyclic-oxy group include,for example, 3-pyrrolidinyloxy, and 4-piperidinyloxy.

Examples of the fused polycyclic non-aromatic heterocyclic-oxy groupinclude, for example, 3-indolynyloxy, and 4-chromanyloxy.

Examples of the hydrocarbon-sulfanyl group include the groups in which ahydrogen atom of the sulfanyl group is substituted with a hydrocarbongroup, and examples of the hydrocarbon include similar groups to theaforementioned hydrocarbon groups. Examples of the hydrocarbon-sulfanylgroups include, for example, alkyl-sulfanyl group, alkenyl-sulfanylgroup, alkynyl-sulfanyl group, cycloalkyl-sulfanyl group,cycloalkyl-alkyl-sulfanyl group and the like, which are aliphatichydrocarbon-sulfanyl groups; aryl-sulfanyl group, and aralkyl-sulfanylgroup.

Examples of the alkyl-sulfanyl group include, for example,methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl,n-butylsulfanyl, isobutylsulfanyl, sec-butylsulfanyl,tert-butylsulfanyl, n-pentylsulfanyl, isopentylsulfanyl,(2-methylbutyl)sulfanyl, (1-methylbutyl)sulfanyl, neopentylsulfanyl,(1,2-dimethylpropyl)sulfanyl, (1-ethylpropyl)sulfanyl, n-hexylsulfanyl,(4-methylpentyl)sulfanyl, (3-methylpentyl)sulfanyl,(2-methylpentyl)sulfanyl, (1-methylpentyl)sulfanyl,(3,3-dimethylbutyl)sulfanyl, (2,2-dimethylbutyl)sulfanyl,(1,1-dimethylbutyl)sulfanyl, (1,2-dimethylbutyl)sulfanyl,(1,3-dimethylbutyl)sulfanyl, (2,3-dimethylbutyl)sulfanyl,(2-ethylbutyl)sulfanyl, (1-ethylbutyl)sulfanyl,(1-ethyl-1-methylpropyl)sulfanyl, n-heptylsulfanyl, n-octylsulfanyl,n-nonylsulfanyl, n-decylsulfanyl, n-undecylsulfanyl, n-dodecylsulfanyl,n-tridecylsulfanyl, n-tetradecylsulfanyl, and n-pentadecylsulfanyl,which are C₁ to C₁₅ straight chain or branched chain alkyl-sulfanylgroups.

Examples of the alkenyl-sulfanyl group include, for example,vinylsulfanyl, (prop-1-en-1-yl)sulfanyl, allylsulfanyl,isopropenylsulfanyl, (but-1-en-1-yl)sulfanyl, (but-2-en-1-yl)sulfanyl,(but-3-en-1-yl)sulfanyl, (2-methylprop-2-en-1-yl)sulfanyl,(1-methylprop-2-en-1-yl)sulfanyl, (pent-1-en-1-yl)sulfanyl,(pent-2-en-1-yl)sulfanyl, (pent-3-en-1-yl)sulfanyl,(pent-4-en-1-yl)sulfanyl, (3-methylbut-2-en-1-yl)sulfanyl,(3-methylbut-3-en-1-yl)sulfanyl, (hex-1-en-1-yl)sulfanyl,(hex-2-en-1-yl)sulfanyl, (hex-3-en-1-yl)sulfanyl,(hex-4-en-1-yl)sulfanyl, (hex-5-en-1-yl)sulfanyl,(4-methylpent-3-en-1-yl)sulfanyl, (4-methylpent-3-en-1-yl)sulfanyl,(hept-1-en-1-yl)sulfanyl, (hept-6-en-1-yl)sulfanyl,(oct-1-en-1-yl)sulfanyl, (oct-7-en-1-yl)sulfanyl,(non-1-en-1-yl)sulfanyl, (non-8-en-1-yl)sulfanyl,(dec-1-en-1-yl)sulfanyl, (dec-9-en-1-yl)sulfanyl,(undec-1-en-1-yl)sulfanyl, (undec-10-en-1-yl)sulfanyl,(dodec-1-en-1-yl)sulfanyl, (dodec-11-en-1-yl)sulfanyl,(tridec-1-en-1-yl)sulfanyl, (tridec-12-en-1-yl)sulfanyl,(tetradec-1-en-1-yl)sulfanyl, (tetradec-13-en-1-yl)sulfanyl,(pentadec-1-en-1-yl)sulfanyl, and (pentadec-14-en-1-yl)sulfanyl, whichare C₂ to C₁₅ straight chain or branched chain alkenyl-sulfanyl groups.

Examples of the alkynyl-sulfanyl group include, for example,ethynylsulfanyl, (prop-1-yn-1-yl)sulfanyl, (prop-2-yn-1-yl)sulfanyl,(but-1-yn-1-yl)sulfanyl, (but-3-yn-1-yl)sulfanyl,(1-methylprop-2-yn-1-yl)sulfanyl, (pent-1-yn-1-yl)sulfanyl,(pent-4-yn-1-yl)sulfanyl, (hex-1-yn-1-yl)sulfanyl,(hex-5-yn-1-yl)sulfanyl, (hept-1-yn-1-yl)sulfanyl,(hept-6-yn-1-yl)sulfanyl, (oct-1-yn-1-yl)sulfanyl,(oct-7-yn-1-yl)sulfanyl, (non-1-yn-1-yl)sulfanyl,(non-8-yn-1-yl)sulfanyl, (dec-1-yn-1-yl)sulfanyl,(dec-9-yn-1-yl)sulfanyl, (undec-1-yn-1-yl)sulfanyl,(undec-10-yn-1-yl)sulfanyl, (dodec-1-yn-1-yl)sulfanyl,(dodec-11-yn-1-yl)sulfanyl, (tridec-1-yn-1-yl)sulfanyl,(tridec-12-yn-1-yl)sulfanyl, (tetradec-1-yn-1-yl)sulfanyl,(tetradec-13-yn-1-yl)sulfanyl, (pentadec-1-yn-1-yl)sulfanyl, and(pentadec-14-yn-1-yl)sulfanyl, which are C₂ to C₁₅ straight chain orbranched chain alkynyl-sulfanyl groups.

Examples of the cycloalkyl-sulfanyl group include, for example,cyclopropylsulfanyl, cyclobutylsulfanyl, cyclopentylsulfanyl,cyclohexylsulfanyl, cycloheptylsulfanyl, and cyclooctylsulfanyl, whichare C₃ to C₈ cycloalkyl-sulfanyl groups.

Examples of the cycloalkyl-alkyl-sulfanyl group include, for example,(cyclopropylmethyl)sulfanyl, (1-cyclopropylethyl)sulfanyl,(2-cyclopropylethyl)sulfanyl, (3-cyclopropylpropyl)sulfanyl,(4-cyclopropylbutyl)sulfanyl, (5-cyclopropylpentyl)sulfanyl,(6-cyclopropylhexyl)sulfanyl, (cyclobutylmethyl)sulfanyl,(cyclopentylmethyl)sulfanyl, (cyclobutylmethyl)sulfanyl,(cyclopentylmethyl)sulfanyl, (cyclohexylmethyl)sulfanyl,(2-cyclohexylethyl)sulfanyl, (3-cyclohexylpropyl)sulfanyl,(4-cyclohexylbutyl)sulfanyl, (cycloheptylmethyl)sulfanyl,(cyclooctylmethyl)sulfanyl, and (6-cyclooctylhexyl)sulfanyl, which areC₄ to C₁₄ cycloalkyl-alkyl-sulfanyl groups.

Examples of the aryl-sulfanyl group include, for example,phenylsulfanyl, 1-naphthylsulfanyl, 2-naphthylsulfanyl, anthrylsulfanyl,fenanthrylsulfanyl, and acenaphthylenylsulfanyl, which are C₆ to C₁₄aryl-sulfanyl groups.

Examples of the aralkyl-sulfanyl group include, for example,benzylsulfanyl, (1-naphthylmethyl)sulfanyl, (2-naphthylmethyl)sulfanyl,(anthracenylmethyl)sulfanyl, (phenanthrenylmethyl)sulfanyl,(acenaphthylenylmethyl)sulfanyl, (diphenylmethyl)sulfanyl,(1-phenethyl)sulfanyl, (2-phenethyl)sulfanyl,(1-(1-naphthyl)ethyl)sulfanyl, (1-(2-naphthyl)ethyl)sulfanyl,(2-(1-naphthyl)ehyl)sulfanyl, (2-(2-naphthyl)ethyl)sulfanyl,(3-phenylpropyl)sulfanyl, (3-(1-naphthyl)propyl)sulfanyl,(3-(2-naphthyl)propyl)sulfanyl, (4-phenylbutyl)sulfanyl,(4-(1-naphthyl)butyl)sulfanyl, (4-(2-naphthyl)butyl)sulfanyl,(5-phenylpentyl)sulfanyl, (5-(1-naphthyl)pentyl)sulfanyl,(5-(2-naphthyl)pentyl)sulfanyl, (6-phenylhexyl)sulfanyl,(6-(1-naphthyl)hexyl)sulfanyl, and (6-(2-naphthyl)hexyl)sulfanyl, whichare C₇ to C₁₆ aralkyl-sulfanyl groups.

Examples of the halogenated alkyl-sulfanyl group include the groups inwhich a hydrogen atom of the sulfanyl group is substituted with ahalogenated alkyl group, and include, for example,(fluoromethyl)sulfanyl, (chloromethyl)sulfanyl, (bromomethyl)sulfanyl,(iodomethyl)sulfanyl, (difluoromethyl)sulfanyl,(trifluoromethyl)sulfanyl, (trichloromethyl)sulfanyl,(2,2,2-trifluoroethyl)sulfanyl, (pentafluoroethyl)sulfanyl,(3,3,3-trifluoropropyl)sulfanyl, (heptafluoropropyl)sulfanyl,(heptafluoroisopropyl)sulfanyl, (nonafluorobutyl)sulfanyl, and(perfluorohexyl)sulfanyl, which are C₁ to C₆ straight chain or branchedchain halogenated alkyl-sulfanyl groups substituted with 1 to 13 halogenatoms.

Examples of the heterocyclic-sulfanyl group include the groups in whicha hydrogen atom of the sulfanyl group is substituted with a heterocyclicgroup, and examples of the heterocyclic ring include similar groups tothe aforementioned heterocyclic groups. Examples of theheterocyclic-sulfanyl group include, for example, a monocyclicheteroaryl-sulfanyl group, a fused polycyclic heteroaryl-sulfanyl group,a monocyclic non-aromatic heterocyclic-sulfanyl group, and a fusedpolycyclic non-aromatic heterocyclic-sulfanyl group.

Examples of the monocyclic heteroaryl-sulfanyl group include, forexample, (imidazol-2-yl)sulfanyl, (1,2,4-triazol-2-yl)sulfanyl,(pyridin-2-yl)sulfanyl, (pyridin-4-yl)sulfanyl, and(pyrimidin-2-yl)sulfanyl.

Examples of the fused polycyclic heteroaryl-sulfanyl group include, forexample, (benzimidazol-2-yl)sulfanyl, (quinolin-2-yl)sulfanyl, and(quinolin-4-yl)sulfanyl.

Examples of the monocyclic non-aromatic heterocyclic-sulfanyl groupsinclude, for example, (3-pyrrolidinyl)sulfanyl, and(4-piperidinyl)sulfanyl.

Examples of the fused polycyclic non-aromatic heterocyclic-sulfanylgroup include, for example, (3-indolinyl)sulfanyl, and(4-chromanyl)sulfanyl.

Examples of the acyl group include, for example, formyl group,glyoxyloyl group, thioformyl group, carbamoyl group, thiocarbamoylgroup, sulfamoyl group, sulfinamoyl group, carboxy group, sulfo group,phosphono group, and groups represented by the following formulas:

wherein R^(a1) and R^(b1) may be the same or different and represent ahydrocarbon group or a heterocyclic group, or R^(a1) and R^(b1) combineto each other, together with the nitrogen atom to which they bind, toform a cyclic amino group.

In the definition of the aforementioned acyl group, among the groupsrepresented by the formula (ω-1A), those groups in which R^(a1) is ahydrocarbon group are referred to as “hydrocarbon-carbonyl group” whoseexamples include, for example, acetyl, propionyl, butyryl, isobutyryl,valeryl, isovaleryl, pivaloyl, lauroyl, myristoryl, palmitoyl, acryloyl,propioloyl, methacryloyl, crotonoyl, isocrotonoyl, cyclohexylcarbonyl,cyclohexylmethylcarbonyl, benzoyl, 1-naphthoyl, 2-naphthoyl, andphenylacetyl, and those groups in which R^(a1) is a heterocyclic groupare referred to as “heterocyclic ring-carbonyl group” whose examplesinclude, for example, 2-thenoyl, 3-furoyl, nicotinoyl, andisonicotinoyl.

Among the groups represented by the formula (ω-2A), those groups inwhich R^(a1) is a hydrocarbon group are referred to as“hydrocarbon-oxy-carbonyl group” whose examples include, for example,methoxycarbonyl, ethoxycarbonyl, phenoxycarbonyl, and benzyloxycarbonyl,and those groups in which R^(a1) is a heterocyclic group are referred toas “heterocyclic ring-oxy-carbonyl group” whose examples include, forexample, 3-pyridyloxycarbonyl.

Among the groups represented by the formula (ω-3A), those groups inwhich R^(a1) is a hydrocarbon group are referred to as“hydrocarbon-carbonyl-carbonyl group” whose examples include, forexample, pyruvoyl, and those groups in which R^(a1) is a heterocyclicgroup are referred to as “heterocyclic ring-carbonyl-carbonyl group.”

Among the groups represented by the formula (ω-4A), those groups inwhich R^(a1) is a hydrocarbon group are referred to as“hydrocarbon-oxy-carbonyl-carbonyl group” whose examples include, forexample, methoxalyl and ethoxalyl groups, and those groups in whichR^(a1) is a heterocyclic group are referred to as “heterocyclicring-oxy-carbonyl-carbonyl group.”

Among the groups represented by the formula (ω-5A), those groups inwhich R^(a1) is a hydrocarbon group are referred to as“hydrocarbon-sulfanyl-carbonyl group,” and those groups in which R^(a1)is a heterocyclic group are referred to as “heterocyclicring-sulfanyl-carbonyl group.”

Among the groups represented by the formula (ω-6A), those groups inwhich R^(a1) is a hydrocarbon group are referred to as“hydrocarbon-thiocarbonyl group,” and those groups in which R^(a1) is aheterocyclic group are referred to as “heterocyclic ring-thiocarbonylgroup.”

Among the groups represented by the formula (ω-7A), those groups inwhich R^(a1) is a hydrocarbon group are referred to as“hydrocarbon-oxy-thiocarbonyl group,” and those groups in which R^(a1)is a heterocyclic group are referred to as “heterocyclicring-oxy-thiocarbonyl group.”

Among the groups represented by the formula (ω-8A), those groups inwhich R^(a1) is a hydrocarbon group are referred to as“hydrocarbon-sulfanyl-thiocarbonyl group,” and those groups in whichR^(a1) is a heterocyclic group are referred to as “heterocyclicring-sulfanyl-thiocarbonyl group.”

Among the groups represented by the formula (ω-9A), those groups inwhich R^(a1) is a hydrocarbon group are referred to as referred to as“N-hydrocarbon-carbamoyl group” whose examples include, for example,N-methylcarbamoyl group, and those groups in which R^(a1) is aheterocyclic group are referred to as “N-heterocyclic ring-carbamoylgroup.”

Among the groups represented by the formula (ω-10A), those groups inwhich both R^(a1) and R^(b1) are hydrocarbon groups are referred to as“N,N-di(hydrocarbon)-carbamoyl group” whose examples include, forexample, N,N-dimethylcarbamoyl group, those groups in which both R^(a1)and R^(b1) are heterocyclic groups are referred to as“N,N-di(heterocyclic ring)-carbamoyl group,” those groups in whichR^(a1) is a hydrocarbon group and R^(b1) is a heterocyclic group arereferred to as “N-hydrocarbon-N-heterocyclic ring-substituted carbamoylgroup,” and those groups in which R^(a1) and R^(b1) combine to eachother, together with the nitrogen atom to which they bind, to form acyclic amino group are referred to as “cyclic amino-carbonyl group”whose examples include, for example, morpholino-carbonyl.

Among the groups represented by the formula (ω-11A), those groups inwhich R^(a1) is a hydrocarbon group are referred to as“N-hydrocarbon-thiocarbamoyl group,” and those groups in which R^(a1) isa heterocyclic group are referred to as “N-heterocyclicring-thiocarbamoyl group.”

Among the groups represented by the formula (ω-12A), those groups inwhich both R^(a1) and R^(b1) are hydrocarbon groups are referred to as“N,N-di(hydrocarbon)-thiocarbamoyl group,” those groups in which bothR^(a1) and R^(b1) are heterocyclic groups are referred to as“N,N-di(heterocyclic ring)-thiocarbamoyl group,” those groups in whichR^(a1) is a hydrocarbon group and R^(b1) is a heterocyclic group arereferred to as “N-hydrocarbon-N-heterocyclic ring-thiocarbamoyl group,”and those groups in which R^(a1) and R^(b1) combine to each other,together with the nitrogen atom to which they bind, to form a cyclicamino group are referred to as “cyclic amino-thiocarbonyl group.”

Among the groups represented by the formula (ω-13A), those groups inwhich R^(a1) is a hydrocarbon group are referred to as“N-hydrocarbon-sulfamoyl group,” and those groups in which R^(a1) is aheterocyclic group are referred to as “N-heterocyclic ring-sulfamoylgroup.”

Among the groups represented by the formula (ω-14A), those groups inwhich both R^(a1) and R^(b1) are hydrocarbon groups are referred to as“N,N-di(hydrocarbon)-sulfamoyl group” whose examples include, forexample, N,N-dimethylsulfamoyl group, those groups in which both R^(a1)and R^(b1) are heterocyclic groups are referred to as“N,N-di(heterocyclic ring)-sulfamoyl group,” those groups in whichR^(a1) is a hydrocarbon group and R^(b1) is a heterocyclic group arereferred to as “N-hydrocarbon-N-heterocyclic ring-sulfamoyl group,” andthose groups in which R^(a1) and R^(b1) combine to each other, togetherwith the nitrogen atom to which they bind, to form a cyclic amino groupare referred to as “cyclic amino-sulfonyl group” whose examples include,for example 1-pyrrolylsulfonyl.

Among the groups represented by the formula (ω-15A), those groups inwhich R^(a1) is a hydrocarbon group are referred to as“N-hydrocarbon-sulfinamoyl group,” and those groups in which R^(a1) is aheterocyclic group are referred to as “N-heterocyclic ring-sulfinamoylgroup.”

Among the groups represented by the formula (ω-16A), those groups inwhich both R^(a1) and R^(b1) are hydrocarbon groups are referred to as“N,N-di(hydrocarbon)-sulfinamoyl group,” those groups in which bothR^(a1) and R^(b1) are heterocyclic groups are referred to as“N,N-di(heterocyclic ring)-sulfinamoyl group,” those groups in whichR^(a1) is a hydrocarbon group and R^(b1) is a heterocyclic group arereferred to as “N-hydrocarbon-N-heterocyclic ring-sulfinamoyl group,”and those groups in which R^(a1) and R^(b1) combine to each other,together with the nitrogen atom to which they bind, to form a cyclicamino group are referred to as “cyclic amino-sulfinyl group.”

Among the groups represented by the formula (ω-17A), those groups inwhich R^(a1) is a hydrocarbon group are referred to as“hydrocarbon-oxy-sulfonyl group,” and those groups in which R^(a1) is aheterocyclic group are referred to as “heterocyclic ring-oxy-sulfonylgroup.”

Among the groups represented by the formula (ω-18A), those groups inwhich R^(a1) is a hydrocarbon group are referred to as“hydrocarbon-oxy-sulfinyl group,” and those groups in which R^(a1) is aheterocyclic group are referred to as “heterocyclic ring-oxy-sulfinylgroup.”

Among the groups represented by the formula (ω-19A), those groups inwhich both R^(a1) and R^(b1) are hydrocarbon groups are referred to as“O,O′-di(hydrocarbon)-phosphono group,” those groups in which bothR^(a1) and R^(b1) are heterocyclic groups are referred to as“O,O′-di(heterocyclic ring)-phosphono group,” and those groups in whichR^(a1) is a hydrocarbon group and R^(b1) is a heterocyclic group arereferred to as “O-hydrocarbon-O′-heterocyclic ring-phosphono group.”

Among the groups represented by the formula (ω-20A), those groups inwhich R^(a1) is a hydrocarbon group are referred to as“hydrocarbon-sulfonyl group” whose examples include, for example,methanesulfonyl and benzenesulfonyl, and those groups in which R^(a1) isa heterocyclic group are referred to as “heterocyclic ring-sulfonylgroup.”

Among the groups represented by the formula (ω-21A), those groups inwhich R^(a1) is a hydrocarbon group are referred to as“hydrocarbon-sulfinyl group” whose examples include, for example,methylsulfinyl and benzenesulfinyl, and those groups in which R^(a1) isa heterocyclic group are referred to as “heterocyclic ring-sulfinylgroup.”

Examples of the hydrocarbon in the groups represented by theaforementioned formulas (ω-1A) through (ω-21A) include the similargroups to the aforementioned hydrocarbon group. Examples of thehydrocarbon-carbonyl group represented by the formula (ω-1A) include,for example, an alkyl-carbonyl group, an alkenyl-carbonyl group, analkynyl-carbonyl group, a cycloalkyl-carbonyl group, acycloalkenyl-carbonyl group, a cycloalkanedienyl-carbonyl group, acycloalkyl-alkyl-carbonyl group, which are aliphatichydrocarbon-carbonyl groups; an aryl-carbonyl group; an aralkyl-carbonylgroup; a bridged cyclic hydrocarbon-carbonyl group; a spirocyclichydrocarbon-carbonyl group; and a terpene family hydrocarbon-carbonylgroup. In the following, groups represented by the formulas (ω-2A)through (ω-21A) are similar to those explained above.

Examples of the heterocyclic ring in the groups represented by theaforementioned formulas (ω-1A) through (ω-21A) include similar groups tothe aforementioned heterocyclic group. Examples of the heterocyclicring-carbonyl group represented by the formula (ω-1A) include, forexample, a monocyclic heteroaryl-carbonyl group, a fused polycyclicheteroaryl-carbonyl group, a monocyclic non-aromatic heterocyclicring-carbonyl group, and a fused polycyclic non-aromatic heterocyclicring-carbonyl group. In the following, groups represented by theformulas (ω-2A) through (ω-21A) are similar to those explained above.

Examples of the cyclic amino in the groups represented by theaforementioned formulas (ω-10A) through (ω-16A) include similar groupsto the aforementioned cyclic amino group.

In the present specification, when a certain functional group is definedas “which may be substituted,” the definition means that the functionalgroup may sometimes have one or more substituents at chemicallysubstitutable positions, unless otherwise specifically mentioned. Kindof substituents, number of substituents, and the position ofsubstituents existing in the functional groups are not particularlylimited, and when two or more substituents exist, they may be the sameor different. Examples of the substituent existing in the functionalgroup include, for example, halogen atoms, oxo group, thioxo group,nitro group, nitroso group, cyano group, isocyano group, cyanato group,thiocyanato group, isocyanato group, isothiocyanato group, hydroxygroup, sulfanyl group, carboxy group, sulfanylcarbonyl group, oxalogroup, methooxalo group, thiocarboxy group, dithiocarboxy group,carbamoyl group, thiocarbamoyl group, sulfo group, sulfamoyl group,sulfino group, sulfinamoyl group, sulfeno group, sulfenamoyl group,phosphono group, hydroxyphosphonyl group, hydrocarbon group,heterocyclic group, hydrocarbon-oxy group, heterocyclic ring-oxy group,hydrocarbon-sulfanyl group, heterocyclic ring-sulfanyl group, acylgroup, amino group, hydrazino group, hydrazono group, diazenyl group,ureido group, thioureido group, guanidino group, carbamoimidoyl group(amidino group), azido group, imino group, hydroxyamino group,hydroxyimino group, aminooxy group, diazo group, semicarbazino group,semicarbazono group, allophanyl group, hydantoyl group, phosphano group,phosphoroso group, phospho group, boryl group, silyl group, stannylgroup, selanyl group, oxido group and the like.

When two or more substituents exist according to the aforementioneddefinition of “which may be substituted,” said two or more substituentsmay combine to each other, together with atom(s) to which they bind, toform a ring. For these cyclic groups, as ring-constituting atoms (ringforming atoms), one to three kinds of one or more hetero atoms selectedfrom oxygen atom, sulfur atom, nitrogen atom and the like may beincluded, and one or more substituents may exist on the ring. The ringmay be monocyclic or fused polycyclic, and aromatic or non-aromatic.

The above substituents according to the aforementioned definition of“which may be substituted” may further be substituted with theaforementioned substituents at the chemically substitutable positions onthe substituent. Kind of substituents, number of substituents, andpositions of substituents are not particularly limited, and when thesubstituents are substituted with two or more substituents, they may bethe same or different. Examples of the substituent include, for example,a halogenated alkyl-carbonyl group whose examples include, for example,trifluoroacetyl, a halogenated alkyl-sulfonyl group whose examplesinclude, for example, trifluoromethanesulfonyl, an acyl-oxy group, anacyl-sulfanyl group, an N-hydrocarbon-amino group, anN,N-di(hydrocarbon)-amino group, an N-heterocyclic ring-amino group, anN-hydrocarbon-N-heterocyclic ring-amino group, an acyl-amino group, anda di(acyl)-amino group. Moreover, substitution on the aforementionedsubstituents may be repeated multiple orders.

Examples of the acyl-oxy group include the groups in which hydrogen atomof hydroxy group is substituted with acyl group, and include, forexample, formyloxy group, glyoxyloyloxy group, thioformyloxy group,carbamoloxy group, thiocarbamoyloxy group, sulfamoyloxy group,sulfinamoloxy group, carboxyoxy group, sulphooxy group, phosphonooxygroup, and groups represented by the following formulas:

wherein R^(a2) and R^(b2) may be the same or different and represent ahydrocarbon group or a heterocyclic group, or R^(a2) and R^(b2) combineto each other, together with the nitrogen atom to which they bind, toform a cyclic amino group.

In the definition of the aforementioned acyl-oxy group, among the groupsrepresented by the formula (ω-1B), those groups in which R^(a2) is ahydrocarbon group are referred to as “hydrocarbon-carbonyl-oxy group”whose examples include, for example, acetoxy and benzoyloxy, and thosegroups in which R^(a2) is a heterocyclic group are referred to as“heterocyclic ring-carbonyl-oxy group.”

Among the groups represented by the formula (ω-2B), those groups inwhich R^(a2) is a hydrocarbon group are referred to as“hydrocarbon-oxy-carbonyl-oxy group,” and those groups in which R^(a2)is a heterocyclic group are referred to as “heterocyclicring-oxy-carbonyl-oxy group.”

Among the groups represented by the formula (ω-3B), those groups inwhich R^(a2) is a hydrocarbon group are referred to as“hydrocarbon-carbonyl-carbonyl-oxy group,” and those groups in whichR^(a2) is a heterocyclic group are referred to as “heterocyclicring-carbonyl-carbonyl-oxy group.”

Among the groups represented by the formula (ω-4B), those groups inwhich R^(a2) is a hydrocarbon group are referred to as“hydrocarbon-oxy-carbonyl-carbonyl-oxy group,” and those groups in whichR^(a2) is a heterocyclic group are referred to as “heterocyclicring-oxy-carbonyl-carbonyl-oxy group.”

Among the groups represented by the formula (ω-5B), those groups inwhich R^(a2) is a hydrocarbon group are referred to as“hydrocarbon-sulfanyl-carbonyl-oxy group,” and those groups where R^(a2)is a heterocyclic group are referred to as “heterocyclicring-sulfanyl-carbonyl-oxy group.”

Among the groups represented by the formula (ω-6B), those groups inwhich R^(a2) is a hydrocarbon group are referred to as“hydrocarbon-thiocarbonyl-oxy group,” and those groups where R^(a2) is aheterocyclic group are referred to as “heterocyclicring-thiocarbonyl-oxy group.”

Among the groups represented by the formula (ω-7B), those groups inwhich R^(a2) is a hydrocarbon group are referred to as“hydrocarbon-oxy-thiocarbonyl-oxy group,” and those groups in whichR^(a2) is a heterocyclic group are referred to as “heterocyclicring-oxy-thiocarbonyl-oxy group.”

Among the groups represented by the formula (ω-8B), those groups inwhich R^(a2) is a hydrocarbon group are referred to as“hydrocarbon-sulfanyl-thiocarbonyl-oxy group,” and those groups whereinR^(a2) is a heterocyclic group are referred to as “heterocyclicring-sulfanyl-thiocarbonyl-oxy group.”

Among the groups represented by the formula (ω-9B), those groups inwhich R^(a2) is a hydrocarbon group are referred to as“N-hydrocarbon-carbamoyl-oxy group,” and those groups in which R^(a2) isa heterocyclic group are referred to as “N-heterocyclicring-carbamoyl-oxy group.”

Among the groups represented by the formula (ω-10B), those groups inwhich both R^(a2) and R^(b2) are hydrocarbon groups are referred to as“N,N-di(hydrocarbon)-carbamoyl-oxy group,” those groups in which bothR^(a2) and R^(b2) are heterocyclic groups are referred to as“N,N-di(heterocyclic ring)-carbamoyl-oxy group,” those groups in whichR^(a2) is a hydrocarbon group and R^(b2) is a heterocyclic group arereferred to as “N-hydrocarbon-N-heterocyclic ring-carbamoyl-oxy group,”and those groups in which R^(a2) and R^(b2) combine to each other,together with the nitrogen atom to which they bind, to form a cyclicicamino group are referred to as “cyclicamino-carbonyl-oxy group.”

Among the groups represented by the formula (ω-11B), those groups inwhich R^(a2) is a hydrocarbon group are referred to as“N-hydrocarbon-thiocarbamoyl-oxy group,” and those groups in whichR^(a2) is a heterocyclic group are referred to as “N-heterocyclicring-thiocarbamoyl-oxy group.”

Among the groups represented by the formula (ω-12B), those groups inwhich both R^(a2) and R^(b2) are hydrocarbon groups are referred to as“N,N-di(hydrocarbon)-thiocarbamoyl-oxy group,” those groups in whichboth R^(a2) and R^(b2) are heterocyclic groups are referred to as“N,N-di(heterocyclic ring)-thiocarbamoyl-oxy group,” those groups inwhich R^(a2) is a hydrocarbon group and R^(b2) is a heterocyclic groupare referred to as “N-hydrocarbon-N-heterocyclic ring-thiocarbamoyl-oxygroup,” and those groups in which R^(a2) and R^(b2) combine to eachother, together with the nitrogen atom to which they bind, to form acyclic amino group are referred to as “cyclicamino-thiocarbonyl-oxygroup.”

Among the groups represented by the formula (ω-13B), those groups inwhich R^(a2) is a hydrocarbon group are referred to as“N-hydrocarbon-sulfamoyl-oxy group,” and those groups in which R^(a2) isa heterocyclic group are referred to as “N-heterocyclicring-sulfamoyl-oxy group.”

Among the groups represented by the formula (ω-14B), those groups inwhich both R^(a2) and R^(b2) are hydrocarbon groups are referred to as“N,N-di(hydrocarbon)-sulfamoyl-oxy group,” those groups in which bothR^(a2) and R^(b2) are heterocyclic groups are referred to as“N,N-di(heterocyclic ring)-sulfamoyl-oxy group,” those groups in whichR^(a2) is a hydrocarbon group and R^(b2) is a heterocyclic group arereferred to as “N-hydrocarbon-N-heterocyclic ring-sulfamoyl-oxy group,”and those groups in which R^(a2) and R^(b2) combine to each other,together with the nitrogen atom to which they bind, to form a cyclicamino group are referred to as “cyclic amino-sulfonyl-oxy group.”

Among the groups represented by the formula (−15B), those groups inwhich R^(a2) is a hydrocarbon group are referred to as“N-hydrocarbon-sulfinamoyl-oxy group,” and those groups where R^(a2) isa heterocyclic group are referred to as “N-heterocyclicring-sulfinamoyl-oxy group.”

Among the groups represented by the formula (ω-16B), those groups inwhich both R^(a2) and R^(b2) are hydrocarbon groups are referred to as“N,N-di(hydrocarbon)-sulfinamoyl-oxy group,” those groups in which bothR^(a2) and R^(b2) are heterocyclic groups are referred to as“N,N-di(heterocyclic ring)-sulfinamoyl-oxy group,” those groups in whichR^(a2) is a hydrocarbon group and R^(b2) is a heterocyclic group arereferred to as “N-hydrocarbon-N-heterocyclic ring-sulfinamoyl-oxygroup,” and those groups in which R^(a2) and R^(b2) combine to eachother, together with the nitrogen atom to which they bind, to form acyclic amino group are referred to as “cyclic amino-sulfinyl-oxy group.”

Among the groups represented by the formula (ω-17B), those groups inwhich R^(a2) is a hydrocarbon group are referred to as“hydrocarbon-oxy-sulfonyl-oxy group,” and those groups in which R^(a2)is a heterocyclic group are referred to as “heterocyclicring-oxy-sulfonyl-oxy group.”

Among the groups represented by the formula (ω-18B), those groups inwhich R^(a2) is a hydrocarbon group are referred to as“hydrocarbon-oxy-sulfinyl-oxy group,” those groups in which R^(a2) is aheterocyclic group are referred to as “heterocyclicring-oxy-sulfinyl-oxy group.”

Among the groups represented by the formula (ω-19B), those groups inwhich both R^(a2) and R^(b2) are hydrocarbon groups are referred to as“O,O′-di(hydrocarbon)-phosphono-oxy group,” those groups in which bothR^(a2) and R^(b2) are heterocyclic groups are referred to as“O,O′-di(heterocyclic ring)-phosphono-oxy group,” and those groups inwhich R^(a2) is a hydrocarbon group and R^(b2) is a heterocyclic groupare referred to as “O-hydrocarbon substituted-O′-heterocyclic ringsubstituted phophono-oxy group.”

Among the groups represented by the formula (ω-20B), those groups inwhich R^(a2) is a hydrocarbon group are referred to as“hydrocarbon-sulfonyl-oxy group,” and those groups in which R^(a2) is aheterocyclic group referred to as “heterocyclic ring-sulfonyl-oxygroup.”

Among the groups represented by the formula (ω-21B), those groups inwhich R^(a2) is a hydrocarbon group are referred to as“hydrocarbon-sulfinyl-oxy group,” and those groups in which R^(a2) is aheterocyclic group are referred to as “heterocyclic ring-sulfinyl-oxygroup.”

Examples of the hydrocarbon in the groups represented by theaforementioned formulas (ω-1B) through (ω-21B) include the similargroups to the aforementioned hydrocarbon group. Examples of thehydrocarbon-carbonyl-oxy group represented by the formula (ω-1B)include, for example, an alkyl-carbonyl-oxy group, analkenyl-carbonyl-oxy group, an alkynyl-carbonyl-oxy group, acycloalkyl-carbonyl-oxy group, a cycloalkenyl-carbonyl-oxy group, acycloalkanedienyl-carbonyl-oxy group, and acycloalkyl-alkyl-carbonyl-oxy group, which are aliphatichydrocarbon-carbonyl-oxy groups; an aryl-carbonyl-oxy group; anaralkyl-carbonyl-oxy group; a bridged cyclic hydrocarbon-carbonyl-oxygroup; a spirocyclic hydrocarbon-carbonyl-oxy group; and a terpenefamily hydrocarbon-carbonyl-oxy group. In the following, groupsrepresented by the formulas (ω-2B) through (ω-21B) are similar to thoseexplained above.

Examples of the heterocyclic ring in the groups represented by theaforementioned formulas (ω-1B) through (ω-21B) include similar groups tothe aforementioned heterocyclic group. Examples of the heterocyclicring-carbonyl group represented by the formula (ω-1B) include, forexample, a monocyclic heteroaryl-carbonyl group, a fused polycyclicheteroaryl-carbonyl group, a monocyclic non-aromatic heterocyclicring-carbonyl group, and a fused polycyclic non-aromatic heterocyclicring-carbonyl group. In the following, groups represented by theformulas (ω-2B) through (ω-21B) are similar to those groups explainedabove.

Examples of the cyclic amino in the groups represented by theaforementioned formulas (ω-10B) through (ω-16B) include similar groupsto the aforementioned cyclic amino group.

The aforementioned acyl-oxy group, hydrocarbon-oxy group, andheterocyclic-oxy group are generically referred to as “substituted oxygroup.” Moreover, these substituted oxy group and hydroxy group aregenerically referred to as “hydroxy group which may be substituted.”

Examples of the acyl-sulfanyl group include the groups in which hydrogenatom of sulfanyl group is substituted with acyl group, and include, forexample, formylsulfanyl group, glyoxyloylsulfanyl group,thioformylsulfanyl group, carbamoyloxy group, thicarbamoyloxy group,sulfamoyloxy group, sulfinamoyloxy group, carboxyoxy group, sulphooxygroup, phosphonooxy group, and groups represented by the followingformulas:

wherein R^(a3) and R^(b3) may be the same or different and represent ahydrocarbon group which may be substituted or a heterocyclic group whichmay be substituted, or R^(a3) and R^(b3) combine to each other, togetherwith the nitrogen atom to which they bind, to form a cyclic amino groupwhich may be substituted.

In the definition of the aforementioned acyl-sulfanyl group, among thegroups represented by the formula (ω-1C), those groups in which R^(a3)is a hydrocarbon group are referred to as “hydrocarbon-carbonyl-sulfanylgroup,” and those groups in which R^(a3) is a heterocyclic group arereferred to as “heterocyclic ring-carbonyl-sulfanyl group.”

Among the groups represented by the formula (ω-2C), those groups inwhich R^(a3) is a hydrocarbon group are referred to as“hydrocarbon-oxy-carbonyl-sulfanyl group,” and those groups in whichR^(a3) is a heterocyclic group are referred to as “heterocyclicring-oxy-carbonyl-sulfanyl group.”

Among the groups represented by the formula (ω-3C), those groups inwhich R^(a3) is a hydrocarbon group are referred to as“hydrocarbon-carbonyl-carbonyl-sulfanyl group,” and those groups inwhich R^(a3) is a heterocyclic group are referred to as “heterocyclicring-carbonyl-carbonyl-sulfanyl group.”

Among the groups represented by the formula (ω-4C), those groups inwhich R^(a3) is a hydrocarbon group are referred to as“hydrocarbon-oxy-carbonyl-carbonyl-sulfanyl group,” and those groups inwhich R^(a3) is a heterocyclic group are referred to as “heterocyclicring-oxy-carbonyl-carbonyl-sulfanyl group.”

Among the groups represented by the formula (ω-5C), those groups inwhich R^(a3) is a hydrocarbon group are referred to as“hydrocarbon-sulfanyl-carbonyl-sulfanyl group,” and those groups inwhich R^(a3) is a heterocyclic group are referred to as “heterocyclicring-sulfanyl-carbonyl-sulfanyl group.”

Among the groups represented by the formula (ω-6C), those groups inwhich R^(a3) is a hydrocarbon group are referred to as“hydrocarbon-thiocarbonyl-sulfanyl group,” and those groups in whichR^(a3) is a heterocyclic group are referred to as “heterocyclicring-thiocarbonyl-sulfanyl group.”

Among the groups represented by the formula (ω-7C), those groups inwhich R^(a3) is a hydrocarbon group are referred to as“hydrocarbon-oxy-thiocarbonyl-sulfanyl group,” and those groups in whichR^(a3) is a heterocyclic group are referred to as “heterocyclicring-oxy-thiocarbonyl-sulfanyl group.”

Among the groups represented by the formula (ω-8C), those groups inwhich R^(a3) is a hydrocarbon group are referred to as“hydrocarbon-sulfanyl-thiocarbonyl-sulfanyl group,” and those groups inwhich R^(a3) is a heterocyclic group are referred to as “heterocyclicring-sulfanyl-thiocarbonyl-sulfanyl group.”

Among the groups represented by the formula (ω-9C), those groups inwhich R^(a3) is a hydrocarbon group are referred to as“N-hydrocarbon-carbamoyl-sulfanyl group,” and those groups in whichR^(a3) is a heterocyclic group are referred to as “N-heterocyclicring-carbamoyl-sulfanyl group.”

Among the groups represented by the formula (ω-10C), those groups inwhich both R^(a3) and R^(b3) are a hydrocarbon groups are referred to as“N,N-di(hydrocarbon)-carbamoyl-sulfanyl group,” those groups in whichboth R^(a3) and R^(b3) are heterocyclic groups are referred to as“N,N-di(heterocyclic ring)-carbamoyl-sulfanyl group,” those groups inwhich R^(a3) is a hydrocarbon group and R^(b3) is a heterocyclic groupare referred to as “N-hydrocarbon-N-heterocyclic ring-carbamoyl-sulfanylgroup,” and those groups in which R^(a3) and R^(b3) combine to eachother, together with the nitrogen atom to which they bind, to form acyclic amino group are referred to as “cyclicamino-carbonyl-sulfamoylgroup.”

Among the groups represented by the formula (ω-11C), those groups inwhich R^(a3) is a hydrocarbon group are referred to as“N-hydrocarbon-thiocarbamoyl-sulfanyl group,” and those groups in whichR^(a3) is a heterocyclic group are referred to as “N-heterocyclicring-thiocarbamoyl-sulfanyl group.”

Among the groups represented by the formula (ω-12C), those groups inwhich both R^(a3) and R^(b3) are hydrocarbon groups are referred to as“N,N-di(hydrocarbon)-thiocarbamoyl-sulfanyl group,” those groups inwhich and R^(a3) and R^(b3) are heterocyclic groups are referred to as“N,N-di(heterocyclic ring)-thiocarbamoyl-sulfanyl group,” those groupsin which R^(a3) is a hydrocarbon group and R^(b3) is a heterocyclicgroup are referred to as “N-hydrocarbon-N-heterocyclicring-thiocarbamoyl-sulfanyl group,” and those groups in which R^(a3) andR^(b3) combine to each other, together with the nitrogen atom to whichthey bind, to form a cyclic amino group are referred to as“cyclicamino-thiocarbonyl-sulfamoyl group.”

Among the groups represented by the formula (ω-13C), those groups inwhich R^(a3) is a hydrocarbon group are referred to as“N-hydrocarbon-sulfamoyl-sulfanyl group,” and those groups in whichR^(a3) is a heterocyclic group are referred to as “N-heterocyclicring-sulfamoyl-sulfanyl group.”

Among the groups represented by the formula (ω-14C), those groups inwhich both R^(a3) and R^(b3) are hydrocarbon groups are referred to as“N,N-di(hydrocarbon)-sulfamoyl-sulfanyl group,” those groups in whichboth R^(a3) and R^(b3) are heterocyclic groups are referred to as“N,N-di(heterocyclic ring)-sulfamoyl-sulfinyl group,” those groups inwhich R^(a3) is a hydrocarbon group and R^(b3) is a heterocyclic groupare referred to as “N-hydrocarbon-N-heterocyclic ring-sulfamoyl-sulfanylgroup,” and those groups in which R^(a3) and R^(b3) combine to eachother, together with the nitrogen atom to which they bind, to form acyclic amino group are referred to as “cyclicamino-sulfonyl-sulfanylgroup.”

Among the groups represented by the formula (ω-15C), those groups inwhich R^(a3) is a hydrocarbon group are referred to as“N-hydrocarbon-sulfinamoyl-sulfanyl group,” and those groups in whichR^(a3) is a heterocyclic group are referred to as “N-heterocyclicring-sulfinamoyl-sulfanyl group.”

Among the groups represented by the formula (ω-16C), those groups inwhich both R^(a3) and R^(b3) are hydrocarbon groups are referred to as“N,N-di(hydrocarbon)-sulfinamoyl-sulfanyl group,” those groups in whichboth R^(a3) and R^(b3) are heterocyclic groups are referred to as“N,N-di(heterocyclic ring)-sulfinamoyl-sulfanyl group,” those groups inwhich R^(a3) is a hydrocarbon group and R^(b3) is a heterocyclic groupare referred to as “N-hydrocarbon-N-heterocyclicring-sulfinamoyl-sulfanyl group,” and those groups in which R^(a3) andR^(b3) combine to each other, together with the nitrogen atom to whichthey bind, to form a cyclic amino group are referred to as“cyclicamino-sulfanyl-sulfanyl group.”

Among the groups represented by the formula (ω-17C), those groups inwhich R^(a3) is a hydrocarbon group are referred to as“hydrocarbon-oxy-sulfonyl-sulfanyl group,” and those groups in whichR^(a3) is a heterocyclic group are referred to as “heterocyclicring-oxy-sulfonyl-sulfanyl group.”

Among the groups represented by the formula (ω-18C), those groups inwhich R^(a3) is a hydrocarbon group are referred to as“hydrocarbon-oxy-sulfinyl-sulfanyl group,” and those groups in whichR^(a3) is a heterocyclic group are referred to as “heterocyclicring-oxy-sulfinyl-sulfanyl group.”

Among the groups represented by the formula (ω-19C), those groups inwhich both R^(a3) and R^(b3) are hydrocarbon groups are referred to as“O,O′-di(hydrocarbon)-phosphono-sulfanyl group,” those groups in whichboth R^(a3) and R^(b3) are heterocyclic groups are referred to as“O,O′-di(heterocyclic ring)-phosphono-sulfanyl group,” and those groupsin which R^(a3) is a hydrocarbon group and R^(b3) is a heterocyclicgroup are referred to as “O-hydrocarbon-O′-heterocyclicring-phosphono-sulfanyl group.”

Among the groups represented by the formula (ω-20C), those groups inwhich R^(a3) is a hydrocarbon group are referred to as“hydrocarbon-sulfonyl-sulfanyl group,” and those groups in which R^(a3)is a heterocyclic group are referred to as “heterocyclicring-sulfonyl-sulfanyl group.”

Among the groups represented by the formula (ω-21C), those groups inwhich R^(a3) is a hydrocarbon group are referred to as“hydrocarbon-sulfinyl-sulfanyl group,” and those groups in which R^(a3)is a heterocyclic group are referred to as “heterocyclicring-sulfinyl-sulfanyl group.”

Examples of the hydrocarbon in the groups represented by theaforementioned formulas (ω-1C) through (ω-21C) include similar groups tothe aforementioned hydrocarbon group. Examples of thehydrocarbon-carbonyl-sulfanyl group represented by the formula (ω-1C)include, for example, an alkyl-carbonyl-sulfanyl group, analkenyl-carbonyl-sulfanyl group, an alkynyl-carbonyl-sulfanyl group, acycloalkyl-carbonyl-sulfanyl group, a cycloalkenyl-carbonyl-sulfanylgroup, a cycloalkanedienyl-carbonyl-sulfanyl group, acycloalkyl-alkyl-carbonyl-sulfanyl group which are aliphatichydrocarbon-carbonyl-sulfanyl groups; an aryl-carbonyl-sulfanyl group;an aralkyl-carbonyl-sulfanyl group; a bridged cyclichydrocarbon-carbonyl-sulfanyl group; a spiro cyclichydrocarbon-carbonyl-sulfanyl group; and a terpene familyhydrocarbon-carbonyl-sulfanyl group. In the following, groupsrepresented by the formulas (ω-2C) through (ω-21C) are similar to thoseexplained above.

Examples of the heterocyclic ring in the groups represented by theaforementioned formulas (ω-1C) through (ω-21C) include similar groups tothe aforementioned heterocyclic group. Examples of the heterocyclicring-carbonyl-sulfanyl group represented by the formula (ω-1C) include,for example, a monocyclic heteroaryl-carbonyl-sulfanyl group, a fusedpolycyclic heteroaryl-carbonyl-sulfanyl group, a monocyclic non-aromaticheterocyclic ring-carbonyl-sulfanyl group, and a fused polycyclicnon-aromatic heterocyclic ring-carbonyl-sulfanyl group. In thefollowing, groups represented by the formula (ω-2C) through (ω-21C) aresimilar to those groups explained above.

Examples of the cyclic amino in the groups represented by theaforementioned formulas (ω-1C) through (ω-16C) include similar groups tothe aforementioned cyclic amino group.

The aforementioned acyl-sulfanyl group, hydrocarbon-sulfanyl group, andheterocyclic-sulfanyl group are generically referred to as “substitutedsulfanyl group.” Moreover, these substituted sulfanyl group and sulfanylgroup are generically referred to as “sulfanyl group which may besubstituted.”

Examples of the N-hydrocarbon-amino group include the groups in whichone hydrogen atom of amino group is substituted with a hydrocarbongroup, and include, for example, an N-alkyl-amino group, anN-alkenyl-amino group, an N-alkynyl-amino group, an N-cycloalkyl-aminogroup, an N-cycloalkyl-alkyl-amino group, an N-aryl-amino group, and anN-aralkyl-amino group.

Examples of the N-alkyl-amino group include, for example, methylamino,ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino,sec-butylamino, tert-butylamino, n-pentylamino, isopentylamino,(2-methylbutyl)amino, (1-methylbutyl)amino, neopentylamino,(1,2-dimethylpropyl)amino, (1-ethylpropyl)amino, n-hexylamino,(4-methylpentyl)amino, (3-methylpentyl)amino, (2-methylpentyl)amino,(1-methylpentyl)amino, (3,3-dimethylbutyl)amino,(2,2-dimethylbutyl)amino, (1,1-dimethylbutyl)amino,(1,2-dimethylbutyl)amino, (1,3-dimethylbutyl)amino,(2,3-dimethylbutyl)amino, (2-ethylbutyl)amino, (1-ethylbutyl)amino,(1-ethyl-1-methylpropyl)amino, n-heptylamino, n-octylamino,n-nonylamino, n-decylamino, n-undecylamino, n-dodecylamino,n-tridecylamino, n-tetradecylamino, and n-pentadecylamino, which are C₁to C₁₅ straight chain or branched chain N-alkyl amino groups.

Examples of the N-alkenyl-amino group include, for example, vinyl amino,(prop-1-en-1-yl)amino, allylamino, isopropenylamino,(but-1-en-1-yl)amino, (but-2-en-1-yl)amino, (but-3-en-1-yl)amino,(2-methylprop-2-en-1-yl)amino, (1-methylprop-2-en-1-yl)amino,(pent-1-en-1-yl)amino, (pent-2-en-1-yl)amino, (pent-3-en-1-yl)amino,(pent-4-en-1-yl)amino, (3-methylbut-2-en-1-yl)amino,(3-methylbut-3-en-1-yl)amino, (hex-1-en-1-yl)amino,(hex-2-en-1-yl)amino, (hex-3-en-1-yl)amino, (hex-4-en-1-yl)amino,(hex-5-en-1-yl)amino, (4-methylpent-3-en-1-yl)amino,(4-methylpent-3-en-1-yl)amino, (hept-1-en-1-yl)amino,(hept-6-en-1-yl)amino, (oct-1-en-1-yl)amino, (oct-7-en-1-yl)amino,(non-1-en-1-yl)amino, (non-8-en-1-yl)amino, (dec-1-en-1-yl)amino,(dec-9-en-1-yl)amino, (undec-1-en-1-yl)amino, (undec-10-en-1-yl)amino,(dodec-1-en-1-yl)amino, (dodec-11-en-1-yl)amino,(tridec-1-en-1-yl)amino, (tridec-12-en-1-yl)amino,(tetradec-1-en-1-yl)amino, (tetradec-13-en-1-yl)amino,(pentadec-1-en-1-yl)amino, and (pentadec-14-en-1-yl)amino, which are C₂to C₁₅ straight chain or branched chain N-alkenyl amino groups.

Examples of the N-alkynyl-amino group include, for example,ethynylamino, (prop-1-yn-1-yl)amino, (prop-2-yn-1-yl)amino,(but-1-yn-1-yl)amino, (but-3-yn-1-yl)amino,(1-methylprop-2-yn-1-yl)amino, (pent-1-yn-1-yl)amino,(pent-4-yn-1-yl)amino, (hex-1-yn-1-yl)amino, (hex-5-yn-1-yl)amino,(hept-1-yn-1-yl)amino, (hept-6-yn-1-yl)amino, (oct-1-yn-1-yl)amino,(oct-7-yn-1-yl)amino, (non-1-yn-1-yl)amino, (non-8-yn-1-yl)amino,(dec-1-yn-1-yl)amino, (dec-9-yn-1-yl)amino, (undec-1-yn-1-yl)amino,(undec-10-yn-1-yl)amino, (dodec-1-yn-1-yl)amino,(dodec-11-yn-1-yl)amino, (tridec-1-yn-1-yl)amino,(tridec-12-yn-1-yl)amino, (tetradec-1-yn-1-yl)amino,(tetradec-13-yn-1-yl)amino, (pentadec-1-yn-1-yl)amino, and(pentadec-14-yn-1-yl)amino, which are C₂ to C₁₅ straight chain orbranched chain N-alkynyl-amino groups.

Examples of the N-cycloalkyl-amino group include, for example,cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino,cycloheptylamino, and cyclooctylamino, which are C₃ to C₈N-cycloalkyl-amino groups.

Examples of the N-cycloalkyl-alkyl-amino group include, for example,(cyclopropylmethyl)amino, (1-cyclopropylethyl)amino,(2-cyclopropylethyl)amino, (3-cyclopropylpropyl)amino,(4-cyclopropylbutyl)amino, (5-cyclopropylpentyl)amino,(6-cyclopropylhexyl)amino, (cyclobutylmethyl)amino,(cyclopentylmethyl)amino, (cyclobutylmethyl)amino,(cyclopentylmethyl)amino, (cyclohexylmethyl)amino,(2-cyclohexylethyl)amino, (3-cyclohexylpropyl)amino,(4-cyclohexylbutyl)amino, (cycloheptylmethyl)amino,(cyclooctylmethyl)amino, and (6-cyclooctylhexyl)amino, which are C₄ toC₁₄ N-cycloalkyl-alkyl-amino groups.

Examples of the N-aryl-amino group include, for example, phenylamino,1-naphthylamino, 2-naphtylamino, anthrylamino, phenanthrylamino, andacenaphthylenylamino, which are C₆ to C₁₄ N-mono-arylamino groups.

Examples of the N-aralkyl-amino group include, for example, benzylamino,(1-naphthylmethyl)amino, (2-naphthylmethyl)amino,(anthracenylmethyl)amino, (phenanthrenylmethyl)amino,(acenaphthylenylmethyl)amino, (diphenylmethyl)amino, (1-phenethyl)amino,(2-phenethyl)amino, (1-(1-naphthyl)ethyl)amino,(1-(2-naphthyl)ethyl)amino, (2-(1-naphthyl)ethyl)amino,(2-(2-naphthyl)ethyl)amino, (3-phenylpropyl)amino,(3-(1-naphthyl)propyl)amino, (3-(2-naphthyl)propyl)amino,(4-phenylbutyl)amino, (4-(1-naphthyl)butyl)amino,(4-(2-naphthyl)butyl)amino, (5-phenylpentyl)amino,(5-(1-naphthyl)pentyl)amino, (5-(2-naphthyl)pentyl)amino,(6-phenylhexyl)amino, (6-(1-naphthyl)hexyl)amino, and(6-(2-naphthyl)hexyl)amino, which are C₇ to C₁₆ N-aralkyl-amino groups.

Examples of the N,N-di(hydrocarbon)-amino group include the groups inwhich two hydrogen atoms of amino group are substituted with hydrocarbongroups, and include, for example, N,N-dimethylamino, N,N-diethylamino,N-ethyl-N-methylamino, N,N-di-n-propylamino, N,N-diisopropylamino,N-allyl-N-methylamino, N-(prop-2-yn-1-yl)-N-methylamino,N,N-dicyclohexylamino, N-cyclohexyl-N-methylamino,N-cyclohexylmethylamino-N-methylamino, N,N-diphenylamino,N-methyl-N-phenylamino, N,N-dibenzylamino, and N-benzyl-N-methylamino.

Examples of the N-heterocyclic ring-amino group include the groups inwhich one hydrogen atom of amino group is substituted with aheterocyclic group, and include, for example, (3-pyrrolizinyl)amino,(4-piperidinyl)amino, (2-tetrahydropyranyl)amino, (3-indolinyl)amino,(4-chromanyl)amino, (3-thienyl)amino, (3-pyridyl)amino,(3-quinolyl)amino, and (5-indolyl)amino.

Examples of the N-hydrocarbon-N-heterocyclic ring-amino group includethe groups in which two hydrogen atoms of amino group are substitutedwith hydrocarbon group and heterocyclic group respectively, and include,for example, N-methyl-N-(4-piperidinyl)amino,N-(4-chromanyl)-N-methylamino, N-methyl-N-(3-thienyl)amino,N-methyl-N-(3-pyridyl)amino, N-methyl-N-(3-quinolyl)amino.

Examples of the acyl-amino group include the groups in which onehydrogen atom of the amino group is substituted with an acyl group, andinclude, for example, formylamino group, glyoxyloylamino group,thioformylamino group, carbamoylamino group, thiocarbamoylamino group,sulfamoylamino group, sulfinamoylamino group, carboxyamino group,sulphoamino group, phosphonoamino group, and groups represented by thefollowing formulas:

wherein R^(a4) and R^(b4) may be the same or different and represent ahydrocarbon group which may be substituted or a heterocyclic group whichmay be substituted, or R^(a4) and R^(b4) combine to each other, togetherwith the nitrogen atom to which they bind, to form a cyclic amino groupwhich may be substituted.

In the definition of the aforementioned acyl-amino group, among thegroups represented by the formula (ω-1D), those groups in which R^(a4)is a hydrocarbon group are referred to as “hydrocarbon-carbonyl-aminogroup,” and those groups in which R^(a4) is a heterocyclic group arereferred to as “heterocyclic ring-carbonyl-amino group.”

Among the groups represented by the formula (ω-2D), those groups inwhich R^(a4) is a hydrocarbon group are referred to as“hydrocarbon-oxy-carbonyl-amino group,” and those groups in which R^(a4)is a heterocyclic group are referred to as “heterocyclicring-oxy-carbonyl-amino group.”

Among the groups represented by the formula (ω-3D), those groups inwhich R^(a4) is a hydrocarbon group are referred to as“hydrocarbon-carbonyl-carbonyl-amino group,” and those groups in whichR^(a4) is a heterocyclic group are referred to as “heterocyclicring-carbonyl-carbonyl-amino group.”

Among the groups represented by the formula (ω-4D), those groups inwhich R^(a4) is a hydrocarbon group are referred to as“hydrocarbon-oxy-carbonyl-carbonyl-amino group,” and those groups inwhich R^(a4) is a heterocyclic group are referred to as “heterocyclicring-oxy-carbonyl-carbonyl-amino group.”

Among the groups represented by the formula (ω-5D), those groups inwhich R^(a4) is a hydrocarbon group are referred to as“hydrocarbon-sulfanyl-carbonyl-amino group,” and those groups in whichR^(a4) is a heterocyclic group are referred to as “heterocyclicring-sulfanyl-carbonyl-amino group.”

Among the groups represented by the formula (ω-6D), those groups inwhich R^(a4) is a hydrocarbon group are referred to as“hydrocarbon-thiocarbonyl-amino group,” and those groups in which R^(a4)is a heterocyclic group are referred to as “heterocyclicring-thiocarbonyl-amino group.”

Among the groups represented by the formula (ω-7D), those groups inwhich R^(a4) is a hydrocarbon group are referred to as“hydrocarbon-oxy-thiocarbonyl-amino group,” and those groups in whichR^(a4) is a heterocyclic group are referred to as “heterocyclicring-oxy-thiocarbonyl-amino group.”

Among the groups represented by the formula (ω-8D), those groups inwhich R^(a4) is a hydrocarbon group are referred to as“hydrocarbon-sulfanyl-thiocarbonyl-amino group,” and those groups inwhich R^(a4) is a heterocyclic group are referred to as “heterocyclicring-sulfanyl-thiocarbonyl-amino group.

Among the groups represented by the formula (ω-9D), those groups inwhich R^(a4) is a hydrocarbon group are referred to as“N-hydrocarbon-carbamoyl group,” and those groups in which R^(a4) is aheterocyclic group are referred to as “N-heterocyclicring-carbamoyl-amino group.”

Among the groups represented by the formula (ω-10D), those groups inwhich both R^(a4) and R^(b4) are hydrocarbon groups are referred to as“N,N-di(hydrocarbon)-carbamoyl-amino group,” those groups in which bothR^(a4) and R^(b4) are heterocyclic groups are referred to as“N,N-di(heterocyclic ring)-carbamoyl-amino group,” those groups in whichR^(a4) is a hydrocarbon group and R^(b4) is a heterocyclic group arereferred to as “N-hydrocarbon-N-heterocyclic ring-carbamoyl-aminogroup,” and those groups in which R^(a4) and R^(b4) combine to eachother, together with the nitrogen atom to which they bind, to form acyclic amino group are referred to as “cyclic amino-carbonyl-aminogroup.”

Among the groups represented by the formula (ω-1D), those groups inwhich R^(a4) is a hydrocarbon group are referred to as“N-hydrocarbon-thiocarbamoyl-amino group,” and those groups in whichR^(a4) is a heterocyclic ring group are referred to as“N-heterocyclic-thiocarbamoyl-amino group.”

Among the groups represented by the formula (ω-12D), those groups inwhich both R^(a4) and R^(b4) are hydrocarbon groups are referred to as“N,N-di(hydrocarbon)-thiocarbamoyl-amino group,” those groups in whichboth R^(a4) and R^(b4) are heterocyclic groups are referred to as“N,N-di(heterocyclic ring)-thiocarbamoyl-amino group,” those groups inwhich R^(a4) is a hydrocarbon group and R^(b4) is a heterocyclic groupare referred to as “N-hydrocarbon-N-heterocyclicring-thiocarbamoyl-amino group,” and those groups in which R^(a4) andR^(b4) combine to each other, together with the nitrogen atom to whichthey bind, to form a cyclic amino group are referred to as “cyclicamino-thiocarbonyl-amino group.”

Among the groups represented by the formula (ω-13D), those groups inwhich R^(a4) is a hydrocarbon group are referred to as“N-hydrocarbon-sulfamoyl-amino group,” and those groups in which R^(a4)is a heterocyclic group are referred to as “N-heterocyclicring-sulfamoyl-amino group.”

Among the groups represented by the formula (ω-14D), those groups inwhich both R^(a4) and R^(b4) are hydrocarbon groups are referred to as“di(hydrocarbon)-sulfamoyl-amino group,” those groups in which bothR^(a4) and R^(b4) are heterocyclic groups are referred to as“N,N-di(heterocyclic ring)-sulfamoyl-amino group,” those groups in whichR^(a4) is a hydrocarbon group and R^(b4) is a heterocyclic group arereferred to as “N-hydrocarbon-N-heterocyclic ring-sulfamoyl-aminogroup,” and those groups in which R^(a4) and R^(b4) combine to eachother, together with the nitrogen atom to which they bind, to form acyclic amino group are referred to as “cyclic amino-sulfonyl-aminogroup.”

Among the groups represented by the formula (ω-15D), those groups inwhich R^(a4) is a hydrocarbon group are referred to as“N-hydrocarbon-sulfinamoyl-amino group,” and those groups in whichR^(a4) is a heterocyclic group are referred to as “N-heterocyclicring-sulfinamoyl-amino group.”

Among the groups represented by the formula (ω-16D), those groups inwhich both R^(a4) and R^(b4) are hydrocarbon groups are referred to as“N,N-di(hydrocarbon)-sulfinamoyl-amino group,” those groups in whichboth R^(a4) and R^(b4) are heterocyclic groups are referred to as“N,N-di(heterocyclic ring)-sulfinamoyl-amino group,” groups in whichR^(a4) is a hydrocarbon group and R^(b4) is a heterocyclic group arereferred to as “N-hydrocarbon-N-heterocyclic ring-sulfinamoyl-aminogroup,” and those groups in which R^(a4) and R^(b4) combine to eachother, together with the nitrogen atom to which they bind, to form acyclic amino group are referred to as “cyclic amino-sulfinyl-aminogroup.”

Among the groups represented by the formula (ω-17D), those groups inwhich R^(a4) is a hydrocarbon group are referred to as“hydrocarbon-oxy-sulfonyl-amino group,” and those groups in which R^(a4)is a heterocyclic group are referred to as “heterocyclicring-oxy-sulfoyl-amino group.”

Among the groups represented by the formula (ω-18D), those groups inwhich R^(a4) is a hydrocarbon group are referred to as“hydrocarbon-oxy-sulfinyl-amino group,” and those groups in which R^(a4)is a heterocyclic group are referred to as “heterocyclicring-oxy-sulfinyl-amino group.”

Among the groups represented by the formula (ω-19D), those groups inwhich both R^(a4) and R^(b4) are hydrocarbon groups are referred to as“O,O′-di(hydrocarbon)-phosphono-amino group,” those groups in which bothR^(a4) and R^(b4) are heterocyclic groups are referred to as“O,O′-di(heterocyclic ring)-phosphono-amino group,” and those groups inwhich R^(a4) is a hydrocarbon group and R^(b4) is a heterocyclic groupare referred to as “O-hydrocarbon-O′-heterocyclic ring-phosphono-aminogroup.”

Among the groups represented by the formula (ω-20D), those groups inwhich R^(a4) is a hydrocarbon group are referred to as“hydrocarbon-sulfonyl-amino group,” and those groups in which R^(a4) isa heterocyclic group are referred to as “heterocyclicring-sulfonyl-amino group.”

Among the groups represented by the formula (ω-21D), those groups inwhich R^(a4) is a hydrocarbon group are referred to as“hydrocarbon-sulfinyl-amino group,” and those groups in which R^(a4) isa heterocyclic group are referred to as “heterocyclicring-sulfinyl-amino group.”

Examples of the hydrocarbon in the groups represented by theaforementioned formulas (ω-1D) through (ω-21D) include the similargroups to the aforementioned hydrocarbon group. Examples of thehydrocarbon-carbonyl-amino groups represented by the formula (ω-1D)include, for example, an alkyl-carbonyl-amino group, analkenyl-carbonyl-amino group, an alkynyl-carbonyl-amino group, acycloalkyl-carbonyl-amino group, a cycloalkenyl-carbonyl-amino group, acycloalkanedienyl-carbonyl-amino group, acycloalkyl-alkyl-carbonyl-amino group which are aliphatichydrocarbon-carbonyl-amino groups; an aryl-carbonyl-amino group; anaralkyl-carbonyl-amino group; a bridged cyclichydrocarbon-carbonyl-amino group; a spiro cyclichydrocarbon-carbonyl-amino group; and a terpene familyhydrocarbon-carbonyl-amino group. In the following, groups representedby the formulas (ω-2D) through (ω-21D) are similar to those explainedabove.

Examples of the heterocyclic ring in the groups represented by theaforementioned formulas (ω-1D) through (ω-21D) include similar groups tothe aforementioned heterocyclic group. Examples of the heterocyclicring-carbonyl-amino group represented by the formula (ω-1D) include, forexample, a monocyclic heteroaryl-carbonyl-amino group, a fusedpolycyclic heteroaryl-carbonyl-amino group, a monocyclic non-aromaticheterocyclic-carbonyl-amino group, and a fused polycyclic non-aromaticheterocyclic-carbonyl-amino group. In the following, groups representedby the formulas (ω-2D) through (ω-21D) are similar to those groupsexplained above.

Examples of the cyclic amino in the groups represented by theaforementioned formulas (ω-10D) through (ω-16D) include similar groupsto the aforementioned cyclic amino group.

Examples of the di(acyl)-amino group include the groups in which twohydrogen atoms of amino group are substituted with acyl groups in thedefinitions of the aforementioned substituents according to “which maybe substituted.” Examples include, for example, di(formyl)-amino group,di(glyoxyloyl)-amino group, di(thioformyl)-amino group,di(carbamoyl)-amino group, di(thiocarbamoyl)-amino group,di(sulfamoyl)-amino group, di(sulfinamoyl)-amino group,di(carboxy)-amino group, di(sulfo)-amino group, di(phosphono)-aminogroup, and groups represented by the following formulas

wherein R^(a5) and R^(b5) may be the same or different and representhydrogen atom, a hydrocarbon group which may be substituted or aheterocyclic group which may be substituted, or R^(a5) and R^(b5)combine to each other, together with the nitrogen atom to which theybind, to form a cyclic amino group which may be substituted.

In the definition of aforementioned di(acyl)-amino group, among thegroups represented by the formula (ω-1E), those groups in which R^(a5)is a hydrocarbon group are referred to as“bis(hydrocarbon-carbonyl)-amino group,” and those groups in whichR^(a5) is a heterocyclic group are referred to as “bis(heterocyclicring-carbonyl)-amino group.”

Among the groups represented by the formula (ω-2E), those groups inwhich R^(a5) is a hydrocarbon group are referred to as“bis(hydrocarbon-oxy-carbonyl)-amino group,” and those groups in whichR^(a5) is a heterocyclic group are referred to as “bis(heterocyclicring-oxy-carbonyl)-amino group.”

Among the groups represented by the formula (ω-3E), those groups inwhich R^(a5) is a hydrocarbon group are referred to as“bis(hydrocarbon-carbonyl-carbonyl)-amino group,” and those groups inwhich R^(a5) is a heterocyclic group are referred to as“bis(heterocyclic ring-carbonyl-carbonyl)-amino group.”

Among the groups represented by the formula (ω-4E), those groups inwhich R^(a5) is a hydrocarbon group are referred to as“bis(hydrocarbon-oxy-carbonyl-carbonyl)-amino group,” and those groupsin which R^(a5) is a heterocyclic group are referred to as“bis(heterocyclic ring-oxy-carbonyl-carbonyl)-amino group.”

Among the groups represented by the formula (ω-5E), those groups inwhich R^(a5) is a hydrocarbon group are referred to as“bis(hydrocarbon-sulfanyl-carbonyl)-amino group,” and those groups inwhich R^(a5) is a heterocyclic group are referred to as“bis(heterocyclic ring-sulfanyl-carbonyl)-amino group.”

Among the groups represented by the formula (ω-6E), those groups inwhich R^(a5) is a hydrocarbon group are referred to as“bis(hydrocarbon-thiocarbonyl)-amino group,” and those groups in whichR^(a5) is a heterocyclic group are referred to as “bis(heterocyclicring-thiocarbonyl)-amino group.”

Among the groups represented by the formula (ω-7E), those groups inwhich R^(a5) is a hydrocarbon group are referred to as“bis(hydrocarbon-oxy-thiocarbonyl)-amino group,” and those groups inwhich R^(a5) is a heterocyclic group are referred to as“bis(heterocyclic ring-oxy-thiocarbonyl)-amino group.”

Among the groups represented by the formula (ω-8E), those groups inwhich R^(a5) is a hydrocarbon group are referred to as“bis(hydrocarbon-sulfanyl-thiocarbonyl)-amino group,” and those groupsin which R^(a5) is a heterocyclic group are referred to as“bis(heterocyclic ring-sulfanyl-thiocarbonyl)-amino group.”

Among the groups represented by the formula (ω-9E), those groups inwhich R^(a5) is a hydrocarbon group are referred to as“bis(N-hydrocarbon-carbamoyl)-amino group,” and those groups in whichR^(a5) is a heterocyclic group are referred to as “bis(N-heterocyclicring-carbamoyl)-amino group.”

Among the groups represented by the formula (ω-10E), those groups inwhich both R^(a5) and R^(b5) are hydrocarbon groups are referred to as“bis[N,N-di(hydrocarbon)-carbamoyl]-amino group,” those groups in whichboth R^(a5) and R^(b5) are heterocyclic groups are referred to as“bis[N,N-di(heterocyclic ring)-carbamoyl]-amino group,” groups in whichR^(a5) is a hydrocarbon group and R^(b5) is a heterocyclic group arereferred to as “bis(N-hydrocarbon-N-heterocyclic ring-carbamoyl)-aminogroup,” and those groups in which R^(a5) and R^(b5) combine to eachother, together with the nitrogen atom to which they bind, to form acyclic amino groups are referred to as “bis(cyclic amino-carbonyl)aminogroup.”

Among the groups represented by the formula (ω-11E), those groups inwhich R^(a5) is a hydrocarbon group are referred to as“bis(N-hydrocarbon-thiocarbamoyl)-amino group,” and those groups inwhich R^(a5) is a heterocyclic group are referred to as“bis(N-heterocyclic ring-thiocarbamoyl)-amino group.”

Among the groups represented by the formula (ω-12E), those groups inwhich both R^(a5) and R^(b5) are hydrocarbon groups are referred to as“bis[N,N-di(hydrocarbon)-thiocarbamoyl]-amino group,” those groups inwhich both R^(a5) and R^(b5) are heterocyclic groups are referred to as“bis[N,N-di(heterocyclic ring)-thiocarbamoyl]-amino group,” those groupsin which R^(a5) is a hydrocarbon group and R^(b5) is a heterocyclicgroup are referred to as “bis(N-hydrocarbon-N-heterocyclicring-thiocarbamoyl)-amino group,” and those groups in which R^(a5) andR^(b5) combine to each other, together with the nitrogen atom to whichthey bind, to form a cyclic amino group are referred to as “bis(cyclicamino-thiocarbonyl)-amino group.”

Among the groups represented by the formula (ω-13E), those groups inwhich R^(a5) is a hydrocarbon group are referred to as“bis(N-hydrocarbon-sulfamoyl)-amino group,” and those groups in whichR^(a5) is a heterocyclic group are referred to as “bis(N-heterocyclicring-sulfamoyl)-amino group.”

Among the groups represented by the formula (ω-14E), those groups inwhich both R^(a5) and R^(b5) are hydrocarbon groups are referred to as“bis[N,N-di(hydrocarbon)-sulfamoyl]-amino group,” those groups in whichboth R^(a5) and R^(b5) are heterocyclic groups are referred to as“bis[N,N-di(heterocyclic ring)-sulfamoyl]-amino group,” those groups inwhich R^(a5) is a hydrocarbon group and R^(b5) is a heterocyclic groupare referred to as “bis(N-hydrocarbon-N-heterocyclicring-sulfamoyl)-amino group,” and those groups in which R^(a5) andR^(b5) combine to each other, together with the nitrogen atom to whichthey bind, to form a cyclic amino group are referred to as “bis(cyclicamino-sulfonyl)amino group.”

Among the groups represented by the formula (ω-15E), those groups inwhich R^(a5) is a hydrocarbon group are referred to as“bis(N-hydrocarbon-sulfinamoyl)-amino group,” and those groups in whichR^(a5) is a heterocyclic group are referred to as “bis(N-heterocyclicring-sulfinamoyl)-amino group.”

Among the groups represented by the formula (ω-16E), those groups inwhich R^(a5) and R^(b5) are hydrocarbon groups are referred to as“bis[N,N-di(hydrocarbon)-sulfinamoyl]-amino group,” those groups inwhich R^(a5) and R^(b5) are heterocyclic groups are referred to as“bis[N,N-di(heterocyclic ring)-sulfinamoyl]-amino group,” those groupsin which R^(a5) is a hydrocarbon group and R^(b5) is a heterocyclicgroup are referred to as “bis(N-hydrocarbon-N-heterocyclicring-sulfinamoyl)-amino group,” and those groups in which R^(a5) andR^(b5) combine to each other, together with the nitrogen atom to whichthey bind, to form a cyclic amino group are referred to as “bis(cyclicamino-sulfinyl)amino group.”

Among the groups represented by the formula (ω-17E), those groups inwhich R^(a5) is a hydrocarbon group are referred to as“bis(hydrocarbon-oxy-sulfonyl)-amino group,” and those groups in whichR^(a5) is a heterocyclic group are referred to as “bis(heterocyclicring-oxy-sulfonyl)-amino group.”

Among the groups represented by the formula (ω-18E), those groups inwhich R^(a5) is a hydrocarbon group are referred to as“bis(hydrocarbon-oxy-sulfinyl)-amino group,” and those groups in whichR^(a5) is a heterocyclic group are referred to as “bis(heterocyclicring-oxy-sulfinyl)-amino group.”

Among the groups represented by the formula (ω-19E), those groups inwhich both R^(a5) and R^(b5) are hydrocarbon groups are referred to as“bis[O,O′-di(hydrocarbon)-phosphono]-amino group,” those groups in whichboth R^(a5) and R^(b5) are heterocyclic groups are referred to as“bis[O,O′-di(heterocyclic ring)-phosphono]-amino group,” and thosegroups in which R^(a5) is a hydrocarbon group and R^(b5) is aheterocyclic group are referred to as “bis(O-hydrocarbon-O′-heterocyclicring-phosphono)-amino group.”

Among the groups represented by the formula (ω-20E), those groups inwhich R^(a5) is a hydrocarbon group are referred to as“bis(hydrocarbon-sulfonyl)-amino group,” and those groups in whichR^(a5) is a heterocyclic group are referred to as “bis(heterocyclicring-sulfonyl)-amino group.”

Among the groups represented by the formula (ω-21E), those groups inwhich R^(a5) is a hydrocarbon group are referred to as“bis(hydrocarbon-sulfinyl)-amino group,” and those groups in whichR^(a5) is a heterocyclic group are referred to as “bis(heterocyclicring-sulfinyl)-amino group.”

Examples of the hydrocarbon in the groups represented by theaforementioned formulas (ω-1E) through (ω-21E) include the similargroups to the aforementioned hydrocarbon group. Examples of thebis(hydrocarbon-carbonyl)-amino groups represented by the formula (ω-1E)include, for example, a bis(alkyl-carbonyl)-amino group, abis(alkenyl-carbonyl)-amino group, a bis(alkynyl-carbonyl)-amino group,a bis(cycloalkyl-carbonyl)-amino group, abis(cycloalkenyl-carbonyl)-amino group, abis(cycloalkanedienyl-carbonyl)-amino group, abis(cycloalkyl-alkyl-carbonyl)-amino group which are bis(aliphatichydrocarbon-carbonyl)-amino groups; a bis(aryl-carbonyl)-amino group; abis(aralkyl-carbonyl)-amino group; a bis(bridged cyclichydrocarbon-carbonyl)-amino group; a bis(spiro cyclichydrocarbon-carbonyl)-amino group; and a bis(terpene familyhydrocarbon-carbonyl)-amino group. In the following, groups representedby the formulas (ω-2E) through (ω-21E) are similar to those explainedabove.

Examples of the heterocyclic ring in the groups represented by theaforementioned formulas (ω-1E) through (ω-21E) include similar groups tothe aforementioned heterocyclic group. Examples of the bis(heterocyclicring-carbonyl)-amino group represented by the formula (ω-1E) include,for example, a bis(monocyclic heteroaryl-carbonyl)-amino group, abis(fused polycyclic heteroaryl-carbonyl)-amino group, a bis(monocyclicnon-aromatic heterocyclic-carbonyl)-amino group, and a bis(fusedpolycyclic non-aromatic heterocyclic-carbonyl)-amino group. In thefollowing, groups represented by the formulas (ω-2E) through (ω-21E) aresimilar to those groups explained above.

Examples of the cyclic amino in the groups represented by theaforementioned formulas (ω-10E) through (ω-16E) include similar groupsto the aforementioned cyclic amino group.

The aforementioned acyl-amino group and di(acyl)-amino group aregenerically referred to as “acyl substituted amino group.” Furthermore,the aforementioned N-hydrocarbon-amino group, N,N-di(hydrocarbon)-aminogroup, N-heterocyclic-amino group, N-hydrocarbon-N-heterocyclic-aminogroup, cyclic amino group, acyl-amino group, and di(acyl)-amino groupare generically referred to as “substituted amino group.”

The compounds represented by the aforementioned general formula (I) areexplained in details.

In the aforementioned general formula (I), examples of “A” includehydrogen atom or acetyl group, and hydrogen atom is preferred.

Examples of the “arene” in “an arene which may have one or moresubstituents in addition to the group represented by formula —O-Awherein A has the same meaning as that defined above and the grouprepresented by formula —CONH-E wherein E has the same meaning as thatdefined above” in the definition of ring Z include a monocyclic or fusedheterocyclic aromatic hydrocarbon, and include, for example, benzenering, naphthalene ring, anthracene ring, phenanthrene ring, andacenaphylene ring. C₆ to C₁₀ arenes such as benzene ring, naphthalenering and the like are preferred, benzene ring, and naphthalene ring aremore preferred, and benzene ring is most preferred.

Examples of the substituent in the definition of “an arene which mayhave one or more substituents in addition to the group represented byformula —O-A wherein A has the same meaning as that defined above andthe group represented by formula —CONH-E wherein E has the same meaningas that defined above” in the aforementioned definition of ring Zinclude similar groups to the substituent explained for the definition“which may be substituted.” The position of substituents existing on thearene is not particularly limited, and when two or more substituentsexist, they may be the same or different.

When “an arene which may have one or more substituents in addition tothe group represented by formula —O-A wherein A has the same meaning asthat defined above and the group represented by formula —CONH-E whereinE has the same meaning as that defined above” in the aforementioneddefinition of ring Z is “a benzene ring which may have one or moresubstituents in addition to the group represented by formula —O-Awherein A has the same meaning as that defined above and the grouprepresented by formula —CONH-E wherein E has the same meaning as thatdefined above,” “a benzene ring which has one to three substituents inaddition to the group represented by formula —O-A wherein A has the samemeaning as that defined above and the group represented by formula—CONH-E wherein E has the same meaning as that defined above” ispreferred, and “a benzene ring which has one substituent in addition tothe group represented by formula —O-A wherein A has the same meaning asthat defined above and the group represented by formula —CONH-E whereinE has the same meaning as that defined above” is more preferred.Preferred examples of said substituents include groups selected from thefollowing Substituent Group γ-1z. A halogen atom and tert-butyl group[(1,1-dimethyl)ethyl group] are more preferred, and a halogen atom ismost preferred. [Substituent Group γ-1z] a halogen atom, nitro group,cyano group, hydroxy group, methoxy group, methyl group, isopropylgroup, tert-butyl group, 1,1,3,3-tetramethylbutyl group,2-phenylethen-1-yl group, 2,2-dicyanoethen-1-yl group,2-cyano-2-(methoxycarbonyl)ethen-1-yl group, 2-carboxy-2-cyanoethen-1-ylgroup, ethynyl group, phenylethynyl group, (trimethylsilyl)ethynylgroup, trifluoromethyl group, pentafluoroethyl group, phenyl group,4-(trifluoromethyl)phenyl group, 4-fluorophenyl group,2,4-difluorophenyl group, 2-phenethyl group, 1-hydroxyethyl group,1-(methoxyimino)ethyl group, 1-[(benzyloxy)imino]ethyl group, 2-thienylgroup [thiophen-2-yl group], 3-thienyl group [thiophen-3-yl group],1-pyrrolyl group [pyrrol-1-yl group], 2-methylthiazol-4-yl group,imidazo[1,2-a]pyridin-2-yl group, 2-pyridyl group [pyridin-2-yl group],acetyl group, isobutyryl group, piperidinocarbonyl group,4-benzylpiperidinocarbonyl group, (pyrrol-1-yl)sulfonyl group, carboxygroup, methoxycarbonyl group,N-[3,5-bis(trifluoromethyl)phenyl]carbamoyl group, N,N-dimethylcarbamoylgroup, sulfamoyl group, N-[3,5-bis(trifluoromethyl)phenyl]sulfamoylgroup, N,N-dimethylsulfamoyl group, amino group, N,N-dimethylaminogroup, acetylamino group, benzoylamino group, methanesulfonylaminogroup, benzenesulfonylamino group, 3-phenylureido group,(3-phenyl)thioureido group, (4-nitrophenyl)diazenyl group, and{[4-(pyridin-2-yl)sulfamoyl]phenyl}diazenyl group

When “an arene which may have one or more substituents in addition tothe group represented by formula —O-A wherein A has the same meaning asthat defined above and the group represented by formula —CONH-E whereinE has the same meaning as that defined above” in the aforementioneddefinition of ring Z is “a benzene ring which may have one or moresubstituents in addition to the group represented by formula —O-Awherein A has the same meaning as that defined above and the grouprepresented by formula —CONH-E wherein E has the same meaning as thatdefined above,” it is most preferable that one substituent exists andlocates on the position of R^(z) when the following partial formula(Iz-1) in the general formula containing ring Z

is represented by the following formula (Iz-2).

In this embodiment, said substituents can be defined as R^(z). Preferredexamples of R^(z) include a group selected from the followingSubstituent Group γ-2z. A halogen atom and tert-butyl group are morepreferred, and a halogen atom is most preferred. [Substituent Groupγ-2z] a halogen atom, nitro group, cyano group, methoxy group, methylgroup, isopropyl group, tert-butyl group, 1,1,3,3-tetramethylbutylgroup, 2-phenylethen-1-yl group, 2,2-dicyanoethen-1-yl group,2-cyano-2-(methoxycarbonyl)ethen-1-yl group, 2-carboxy-2-cyanoethen-1-ylgroup, ethynyl group, phenylethynyl group, (trimethylsilyl)ethynylgroup, trifluoromethyl group, pentafluoroethyl group, phenyl group,4-(trifluoromethyl)phenyl group, 4-fluorophenyl group,2,4-difluorophenyl group, 2-phenethyl group, 1-hydroxyethyl group,1-(methoxyimino)ethyl group, 1-[(benzyloxy)imino]ethyl group, 2-thienylgroup, 3-thienyl group, 1-pyrrolyl group, 2-methylthiazol-4-yl group,imidazo[1,2-a]pyridin-2-yl group, 2-pyridyl group, acetyl group,isobutyryl group, piperidinocarbonyl group, 4-benzylpiperidinocarbonylgroup, (pyrrol-1-yl)sulfonyl group, carboxy group, methoxycarbonylgroup, N-[3,5-bis(trifluoromethyl)phenyl]carbamoyl group,N,N-dimethylcarbamoyl group, sulfamoyl group,N-[3,5-bis(trifluoromethyl)phenyl]sulfamoyl group, N,N-dimethylsulfamoylgroup, amino group, N,N-dimethylamino group, acetylamino group,benzoylamino group, methanesulfonylamino group, benzenesulfonylaminogroup, 3-phenylureido group, (3-phenyl)thioureido group,(4-nitrophenyl)diazenyl group, and{[4-(pyridin-2-yl)sulfamoyl]phenyl}diazenyl group

When “an arene which may have one or more substituents in addition tothe group represented by formula —O-A wherein A has the same meaning asthat defined above and the group represented by formula —CONH-E whereinE has the same meaning as that defined above” in the aforementioneddefinition of ring Z is “a naphthalene ring which may have one or moresubstituents in addition to the group represented by formula —O-Awherein A has the same meaning as that defined above and the grouprepresented by formula —CONH-E wherein E has the same meaning as thatdefined above,” naphthalene ring is preferred.

Examples of the “hetero arene” in “a hetero arene which may have one ormore substituents in addition to the group represented by formula —O-Awherein A has the same meaning as that defined above and the grouprepresented by formula —CONH-E wherein E has the same meaning as thatdefined above” in the aforementioned definition of ring Z include amonocyclic or a fused polycyclic aromatic heterocyclic rings containingat least one of 1 to 3 kinds of heteroatoms selected from oxygen atom,sulfur atom and nitrogen atom and the like as ring-constituting atoms(ring forming atoms), and include, for example, furan ring, thiophenering, pyrrole ring, oxazole ring, isoxazole ring, thiazole ring,isothiazole ring, imidazole ring, pyrazole ring, 1,2,3-oxadiazole ring,1,2,3-thiadiazole ring, 1,2,3-triazole ring, pyridine ring, pyridazinering, pyrimidine ring, pyrazine ring, 1,2,3-triazine ring,1,2,4-triazine ring, 1H-azepine ring, 1,4-oxepine ring, 1,4-thiazepinering, benzofuran ring, isobenzofuran ring, benzo[b]thiophene ring,benzo[c]thiophene ring, indole ring, 2H-isoindole ring, 1H-indazolering, 2H-indazole ring, benzoxazole ring, 1,2-benzisoxazole ring,2,1-benzisoxazole ring, benzothiazole ring, 1,2-benzisothiazole ring,2,1-benzisothiazole ring, 1,2,3-benzoxadiazol ring, 2,1,3-benzoxadiazolring, 1,2,3-benzothiadiazole ring, 2,1,3-benzothiadiazole ring,1H-benzotriazole ring, 2H-benzotriazole ring, quinoline ring,isoquinoline ring, cinnoline ring, quinazoline ring, quinoxaline ring,phthalazine ring, naphthyridine ring, 1H-1,5-benzodiazepine ring,carbazole ring, α-carboline ring, β-carboline ring, γ-carboline ring,acridine ring, phenoxazine ring, phenothiazine ring, phenazine ring,phenanthridine ring, phenanthroline ring, thianthrene ring, indolizinering, and phenoxathiine ring, which are 5 to 14-membered monocyclic orfused polycyclic aromatic heterocyclic rings. 5 to 10-memberedmonocyclic or fused polycyclic aromatic heterocyclic rings arepreferred, and thiophene ring, pyridine ring, indole ring, andquinoxaline ring are more preferred.

Examples of the substituent in the definition of “a hetero arene whichmay have one or more substituents in addition to the group representedby formula —O-A wherein A has the same meaning as that defined above andthe group represented by formula —CONH-E wherein E has the same meaningas that defined above” in the aforementioned definition of ring Zinclude similar groups to the substituent explained for theaforementioned definition “which may be substituted.” The position ofsubstituents existing on the hetero arene is not particularly limited,and when two or more substituents exist, they may be the same ordifferent.

A halogen atom is preferred as the substituent in the definition of “ahetero arene which may have one or more substituents in addition to thegroup represented by formula —O-A wherein A has the same meaning as thatdefined above and the group represented by formula —CONH-E wherein E hasthe same meaning as that defined above” in the aforementioned definitionof ring Z.

Examples of the substituent in the definition of “a 2,5-di-substitutedphenyl group” in the definition of E include similar groups to thesubstituent explained for the definition “which may be substituted.”

Preferred examples of the “2,5-di-substituted phenyl group” in thedefinition of E include groups represented by the following SubstituentGroup δ-1e. [Substituent Group δ-1e] 2,5-dimethoxyphenyl group,2-chloro-5-(trifluoromethyl)phenyl group, 2,5-bis(trifluoromethyl)phenylgroup, 2-fluoro-5-(trifluoromethyl)phenyl group,2-nitro-5-(trifluoromethyl)phenyl group,2-methyl-5-(trifluoromethyl)phenyl group,2-methoxy-5-(trifluoromethyl)phenyl group,2-methylsulfanyl-5-(trifluoromethyl)phenyl group,2-(1-pyrrolidinyl)-5-(trifluoromethyl)phenyl group,2-morpholino-5-(trifluoromethyl)phenyl group, 2,5-dichlorophenyl group,2,5-bis[(1,1-dimethyl)ethyl]phenyl group,5-[(1,1-dimethyl)ethyl]-2-methoxyphenyl group, 4-methoxybiphenyl-3-ylgroup, 2-bromo-5-(trifluoromethyl)phenyl group,2-(2-naphthyloxy)-5-(trifluoromethyl)phenyl group,2-(2,4-dichlorophenoxy)-5-(trifluoromethyl)phenyl group,2-[4-(trifluoromethyl)piperidin-1-yl]-5-(trifluoromethyl)phenyl group,2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl group,2-(2-methoxyphenoxy)-5-(trifluoromethyl)phenyl group,2-(4-chloro-3,5-dimethylphenoxy)-5-(trifluoromethyl)phenyl group,2-piperidino-5-(trifluoromethyl)phenyl group,2-(4-methylphenoxy)-5-(trifluoromethyl)phenyl group,2-(4-chlorophenoxy)-5-(trifluoromethyl)phenyl group,5-isopropyl-2-methylphenyl group, 2,5-diethoxyphenyl group,2,5-dimethylphenyl group, 5-chloro-2-cyano group,5-diethylsulfamoyl-2-methoxyphenyl group, 2-chloro-5-nitrophenyl group,2-methoxy-5-(phenylcarbamoyl)phenyl group, 5-acetylamino-2-methoxyphenylgroup, 5-methoxy-2-methylphenyl group, 2,5-dibutoxyphenyl group,2,5-diisopentyloxy group, 5-carbamoyl-2-methoxyphenyl group,5-[(1,1-dimethyl)propyl]-2-phenoxyphenyl group,2-hexyloxy-5-methanesulfonyl group,5-(2,2-dimethylpropionyl)-2-methylphenyl group,5-methoxy-2-(1-pyrrolyl)phenyl group,5-chloro-2-(p-toluenesulfonyl)phenyl group,2-chloro-5-(p-toluenesulfonyl)phenyl group, 2-fluoro-5-methanesulfonylgroup, 2-methoxy-5-phenoxy group,2-methoxy-5-(1-methyl-1-phenylethyl)phenyl group,5-morpholino-2-nitrophenyl group, 5-fluoro-2-(1-imidazolyl)phenyl group,2-butyl-5-nitrophenyl group, 5-[(1,1-dimethyl)propyl]-2-hydroxyphenylgroup, 2-methoxy-5-methylphenyl group, 2,5-difluorophenyl group,2-benzoyl-5-methylphenyl group,2-(4-cyanophenoxy)-5-(trifluoromethyl)phenyl group, and2-(4-methoxyphenoxy)-5-(trifluoromethyl)phenyl group

“A 2,5-di-substituted phenyl group wherein at least one of saidsubstituents is trifluoromethyl group” is more preferred, a groupselected from the following Substituent Group δ-2e is further preferred,and 2,5-bis(trifluoromethyl)phenyl group is most preferred. [SubstituentGroup δ-2e] 2-chloro-5-(trifluoromethyl)phenyl group,2,5-bis(trifluoromethyl)phenyl group, 2-fluoro-5-(trifluoromethyl)phenylgroup, 2-nitro-5-(trifluoromethyl)phenyl group,2-methyl-5-(trifluoromethyl)phenyl group,2-methoxy-5-(trifluoromethyl)phenyl group,2-methylsulfanyl-5-(trifluoromethyl)phenyl group,2-(1-pyrrolidinyl)-5-(trifluoromethyl)phenyl group,2-morpholino-5-(trifluoromethyl)phenyl group,2-bromo-5-(trifluoromethyl)phenyl group,2-(2-naphthyloxy)-5-(trifluoromethyl)phenyl group,2-(2,4-dichlorophenoxy)-5-(trifluoromethyl)phenyl group,2-[4-(trifluoromethyl)piperidin-1-yl]-5-(trifluoromethyl)phenyl group,2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl group,2-(2-methoxyphenoxy)-5-(trifluoromethyl)phenyl group,2-(4-chloro-3,5-dimethylphenoxy)-5-(trifluoromethyl)phenyl group,2-piperidino-5-(trifluoromethyl)phenyl group,2-(4-methylphenoxy)-5-(trifluoromethyl)phenyl group,2-(4-chlorophenoxy)-5-(trifluoromethyl)phenyl group,2-(4-cyanophenoxy)-5-(trifluoromethyl)phenyl group, and2-(4-methoxyphenoxy)-5-(trifluoromethyl)phenyl group

Examples of the substituent in the definition of “a 3,5-di-substitutedphenyl group” in the definition of E include similar groups to thesubstituent explained for the definition “which may be substituted.”

Preferred examples of the “3,5-di-substituted phenyl group” in thedefinition of E include groups represented by the following SubstituentGroup δ-3e. [Substituent Group δ-3e] 3,5-bis(trifluoromethyl)phenylgroup, 3,5-dichlorophenyl group, 3,5-bis[(1,1-dimethyl)ethyl]phenylgroup, 3-fluoro-5-(trifluoromethyl)phenyl group,3-bromo-5-(trifluoromethyl)phenyl group,3-methoxy-5-(trifluoromethyl)phenyl group, 3,5-difluorophenyl group,3,5-dinitrophenyl group, 3,5-dimethylphenyl group, 3,5-dimethoxyphenylgroup, 3,5-bis(methoxycarbonyl)phenyl group,3-methoxycarbonyl-5-(trifluoromethyl)phenyl group,3-carboxy-5-(trifluoromethyl)phenyl group, and 3,5-dicarboxyphenyl group

“A 3,5-di-substituted phenyl group wherein at least one of saidsubstituents is trifluoromethyl group” is more preferred, a groupselected from the following Substituent Group δ-4e is further preferred,and 3,5-bis(trifluoromethyl)phenyl group is most preferred.

[Substituent Group δ-4e] 3,5-bis(trifluoromethyl)phenyl group,3-fluoro-5-(trifluoromethyl)phenyl group,3-bromo-5-(trifluoromethyl)phenyl group,3-methoxy-5-(trifluoromethyl)phenyl group,3-methoxycarbonyl-5-(trifluoromethyl)phenyl group, and3-carboxy-5-(trifluoromethyl)phenyl group

Examples of the substituent in the definition of “a monocyclic or afused polycyclic heteroaryl group which may be substituted, providedthat the compound wherein said heteroaryl group is {circle around (1)} afused polycyclic heteroaryl group wherein the ring which binds directlyto —CONH— group is a benzene ring, {circle around (2)} unsubstitutedthiazol-2-yl group, or {circle around (3)} unsubstitutedbenzothiazol-2-yl group is excluded” in the aforementioned definition ofE include similar groups to the substituent explained for the definition“which may be substituted.” The position of substituents existing on theheteroaryl group is not particularly limited, and when two or moresubstituents exist, they may be the same or different.

Examples of the “monocyclic heteroaryl group” in “a monocyclic or afused polycyclic heteroaryl group which may be substituted” in theaforementioned definition of E include similar groups to the “monocyclicheteroaryl group” in the definition of the aforementioned “heterocyclicgroup.”

Examples of the “fused polycyclic heteroaryl group” in “a monocyclic ora fused polycyclic heteroaryl group which may be substituted” in theaforementioned definition of E include similar groups to the “fusedpolycyclic heteroaryl group” in the definition of the aforementioned“heterocyclic group.”

As “a monocyclic or a fused polycyclic heteroaryl group which may besubstituted” in the aforementioned definition of E, {circle around (1)}a fused polycyclic heteroaryl group wherein the ring which bindsdirectly to —CONH— group in the general formula (I) is a benzene ring,{circle around (2)} unsubstituted thiazol-2-yl group, and {circle around(3)} unsubstituted benzothiazol-2-yl group are excluded.

A 5 to 10-membered monocyclic or fused polycyclic heteroaryl group ispreferred as “a monocyclic or a fused polycyclic heteroaryl group” in “amonocyclic or a fused polycyclic heteroaryl group which may besubstituted” in the aforementioned definition of E, and preferredexamples of the group include thiazolyl group, thienyl group, pyrazolylgroup, oxazolyl group, 1,3,4-thiadiazolyl group, pyridyl group,pyrimidinyl group, pyrazinyl group, and quinolyl group.

A 5-membered monocyclic heteroaryl group is more preferred as “amonocyclic or a fused polycyclic heteroaryl group” in “a monocyclic or afused polycyclic heteroaryl group which may be substituted” in theaforementioned definition of E. Thiazolyl group, thienyl group,pyrazolyl group, oxazolyl group, and 1,3,4-thiadiazolyl group arefurther preferred, and thiazolyl group is most preferred.

A substituted thiazolyl group is most preferred as said “a monocyclic ora fused polycyclic heteroaryl group which may be substituted,” becauseunsubstituted thiazol-2-yl group is excluded as “a monocyclic or a fusedpolycyclic heteroaryl group which may be substituted.”

When “a monocyclic or a fused polycyclic heteroaryl group which may besubstituted” in the aforementioned definition of E is “a substitutedthiazolyl group,” “a mono-substituted thiazol-2-yl group” and “adi-substituted thiazol-2-yl group” are preferred, and “a di-substitutedthiazol-2-yl group” is further preferred.

When “a monocyclic or a fused polycyclic heteroaryl group which may besubstituted” in the aforementioned definition of E is “a di-substitutedthiazol-2-yl group,” a group selected from the following SubstituentGroup δ-5e is further preferred, and4-[(1,1-dimethyl)ethyl]-5-[(2,2-dimethyl)propionyl]thiazol-2-yl group ismost preferred.

[Substituent Group δ-5e] 5-bromo-4-[(1,1-dimethyl)ethyl]thiazol-2-ylgroup, 5-bromo-4-(trifluoromethyl)thiazol-2-yl group,5-cyano-4-[(1,1-dimethyl)ethyl]thiazol-2-yl group, 5-methylthiazol-2-ylgroup, 4,5-dimethylthiazol-2-yl group, 5-methyl-4-phenylthiazol-2-ylgroup, 5-(4-fluorophenyl)-4-methylthiazol-2-yl group,4-methyl-5-[3-(trifluoromethyl)phenyl]thiazol-2-yl group,4-[(1,1-dimethyl)ethyl]-5-ethylthiazol-2-yl group,4-ethyl-5-phenylthiazol-2-yl group, 4-isopropyl-5-phenylthiazol-2-ylgroup, 4-butyl-5-phenylthiazol-2-yl group,4-[(1,1-dimethyl)ethyl]-5-[(2,2-dimethyl)propionyl]thiazol-2-yl group,4-[(1,1-dimethyl)ethyl]-5-(ethoxycarbonyl)thiazol-2-yl group,4-[(1,1-dimethyl)ethyl]-5-piperidinothiazol-2-yl group,4-[(1,1-dimethyl)ethyl]-5-morpholinothiazol-2-yl group,4-[(1,1-dimethyl)ethyl]-5-(4-methylpiperazin-1-yl)thiazol-2-yl group,4-[(1,1-dimethyl)ethyl]-5-(4-phenylpiperazin-1-yl)thiazol-2-yl group,5-carboxymethyl-4-phenylthiazol-2-yl group, 4,5-diphenylthiazol-2-ylgroup, 4-benzyl-5-phenylthiazol-2-yl group,5-phenyl-4-(trifluoromethyl)thiazol-2-yl group,5-acetyl-4-phenylthiazol-2-yl group, 5-benzoyl-4-phenylthiazol-2-ylgroup, 5-ethoxycarbonyl-4-phenylthiazol-2-yl group,5-ethoxycarbonyl-4-(pentafluorophenyl)thiazol-2-yl group,5-methylcarbamoyl-4-phenylthiazol-2-yl group,5-ethylcarbamoyl-4-phenylthiazol-2-yl group,5-isopropylcarbamoyl-4-phenylthiazol-2-yl group,5-(2-phenylethyl)carbamoyl-4-phenylthiazol-2-yl group,5-ethoxycarbonyl-4-(trifluoromethyl)thiazol-2-yl group,5-carboxy-4-[(1,1-dimethyl)ethyl]thiazol-2-yl group,5-(ethoxycarbonyl)methyl-4-phenylthiazol-2-yl group,5-carboxy-4-phenylthiazol-2-yl group, and5-propylcarbamoyl-4-phenylthiazol-2-yl group.

When “a monocyclic or a fused polycyclic heteroaryl group which may besubstituted” in the aforementioned definition of E is “amono-substituted thiazol-2-yl group,” preferred examples of the groupinclude groups represented by the following Substituent Group δ-6e.

[Substituent Group δ-6e] 4-[(1,1-dimethyl)ethyl]thiazol-2-yl group,4-phenylthiazol-2-yl group,4-[3,5-bis(trifluoromethyl)phenyl]thiazol-2-yl group,4-(2,4-dichlorophenyl)thiazol-2-yl group,4-(3,4-dichlorophenyl)thiazol-2-yl group,4-[4-(trifluoromethyl)phenyl]thiazol-2-yl group,4-(2,5-difluorophenyl)thiazol-2-yl group,4-(4-methoxyphenyl)thiazol-2-yl group,4-[3-(trifluoromethyl)phenyl]thiazol-2-yl group, and4-(pentafluorophenyl)thiazol-2-yl group

Compounds other than “substituted benzoic acid derivatives representedby the following general formula (X-1)” are preferred as the compoundrepresented by the general formula (I).

wherein R¹⁰⁰¹ represents the following general formula (X-2):

or the following general formula (X-3):

wherein each of R¹⁰⁰3, R¹⁰⁰⁴ and R¹⁰⁰⁵ independently represents hydrogenatom, an alkyl group having from 1 to 6 carbons or an alkoxy grouphaving from 1 to 6 carbons, each of R¹⁰⁰⁹ and R¹⁰¹⁰ independentlyrepresents hydrogen atom, an alkyl group having from 1 to 6 carbons, oran acyl group having from 2 to 11 carbons; R¹⁰⁰² represents hydrogenatom, a lower alkyl group having from 1 to 6 carbons, which may besubstituted, an aryl group having from 6 to 12 carbons, which may besubstituted, a heteroaryl group having from 4 to 11 carbons, which maybe substituted, an aralkyl group having from 7 to 14 carbons, which maybe substituted, a heteroarylalkyl group having from 5 to 13 carbons,which may be substituted, or an acyl group having from 2 to 11 carbons;X¹⁰⁰¹ represents carboxy group which may be esterified or amidated.

The compounds represented by the aforementioned general formula (I) mayform salts. Examples of pharmacologically acceptable salts include, whenacidic groups exist, metal salts such as lithium salt, sodium salt,potassium salt, magnesium salt, calcium salts, or ammonium salts such asammonium salt, methylammonium salt, dimethylammonium salt,trimethylammonium salt, dicyclohexylammonium salt, and when basic groupsexist, mineral acid salts such as hydrochloride, oxalate, hydrosulfate,nitrate, phosphate, or organic acid salts such as methane sulfonate,benzene sulfonate, para-toluene sulfonate, acetate, propionate,tartrate, fumarate, maleate, malate, oxalate, succinate, citrate,benzoate, mandelate, cinnamate, lactate. Salts may sometimes be formedwith amino acids such as glycine. As active ingredients of themedicament of the present invention, pharmacologically acceptable saltsmay also be suitably used.

The compounds or salts thereof represented by the aforementioned generalformula (I) may exist as hydrates or solvates. As active ingredients ofthe medicament of the present invention, any of the aforementionedsubstances may be used. Furthermore, the compounds represented by theaforementioned general formula (I) may sometimes have one or moreasymmetric carbons, and may exist as steric isomers such as opticallyactive substance and diastereomer. As active ingredients of themedicament of the present invention, pure forms of stereoisomers,arbitrary mixture of enantiomers or diastereomers, and racemates may beused.

Furthermore, when the compounds represented by the general formula (I)has, for example, 2-hydroxypyridine form, the compounds may exist as2-pyridone form which is a tautomer. As active ingredients of themedicament of the present invention, pure forms of tautomers or amixture thereof may be used. When the compounds represented by thegeneral formula (I) have olefinic double bonds, the configuration may bein either E or Z, and as active ingredients of the medicament of thepresent invention, geometrical isomer in either of the configurations ora mixture thereof may be used.

Examples of the compounds included in the general formula (I) as activeingredients of the medicaments of the present invention are shown below.However, the active ingredients of the medicaments of the presentinvention are not limited to the compound set out below.

The abbreviations used in the following tables have the followingmeanings.

Me: methyl group, Et: ethyl group.

Compound Number

E 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

268

The compounds represented by the general formula (I) can be prepared,for example, by a method described in the following reaction scheme.

wherein each of A, ring Z, and E has the same meaning as that defined inthe general formula (I), A¹⁰¹ represents a hydrogen atom or protectinggroups of hydroxy group (preferably, an alkyl group such as methyl groupand the like; an aralkyl group such as benzyl group and the like; anacetyl group, an alkoxyalkyl group such as methoxymethyl group and thelike; a substituted silyl group such as trimethylsilyl group or thelike), each of R and R¹⁰¹ represents a hydrogen atom, a C₁ to C₆ alkylgroup or the like, E¹⁰¹ represents E or precursor of E in the definitionof the general formula (I), G represents a hydroxy group, halogen atoms(preferably, a chlorine atom), a hydrocarbon-oxy group (preferably, anaryl-oxy group which may be substituted by halogen atom), an acyl-oxygroup, an imido-oxy group or the like.(First Step)

The amide (3) can be prepared by dehydrocondensation of the carboxylicacid derivative (1) and the amine (2). This reaction is carried out at areaction temperature of from 0° C. to 180° C., without solvent or in anaprotic solvent, in the presence of an acid halogenating agent or adehydrocondensing agent, and in the presence or absence of a base.

As the halogenating agent, examples include, for example, thionylchloride, thionyl bromide, sulfuryl chloride, phosphorus oxychloride,phosphorus trichloride, phosphorus pentachloride or the like. When A¹⁰¹is hydrogen atom, phosphorus trichloride is preferable, and when A¹⁰¹ isacetyl group or the like, phosphorus oxychloride is preferable. As thedehydrocondensing agent, examples include, for example,N,N′-dicyclohexylcarbodiimide,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride,diphenylphosphorylazide or the like. As the base, examples includeinorganic bases such as sodium carbonate, potassium carbonate, sodiumhydrogencarbonate or the like, or organic bases such as pyridine,triethylamine, N,N′-diethylaniline or the like. As the aprotic solvent,examples include dichloromethane, dichloroethane, chloroform,tetrahydrofuran, 1,4-dioxane, benzene, toluene, monochlorobenzene,o-dichlorobenzene, N,N′-dimethylformamide, N-methylpyrrolidone or thelike, when the reaction is carried out in the presence of the acidhalogenating agent, particularly, toluene, monochlorobenzene,o-dichlorobenzene are preferable.

A target compound can also be prepared, for example, by a method orsimilar method described in Journal of Medicinal Chemistry, (USA), 1998,Vol. 41, No. 16, p. 2939-2945, in which the acid chloride is preparedand isolated beforehand from carboxylic acid, then the result is made toreact with an amine having E¹⁰¹.

When G is hydroxy group, the reaction condition described in Archiv derPharmazie, (Germany), 1998, Vol. 331, No. 1, p. 3-6 can be used as apreferred reaction condition.

Kinds of carboxylic acid derivative (1) and amine (2) are notparticularly limited, and new compounds synthesized by referring towell-known preparation method described in the literature orcommercially available reagents can be used for the aforementionedreaction.

(Second Step)

When the amide (3) has a protecting group and/or has a favorablesubstituent for functional group modification, for example, an aminogroup and a protected amino group or its precursor; a carboxy group anda protected carboxy group or its precursor; a hydroxy group and aprotected hydroxy group or its precursor, the final target compound (4)can be prepared by a reaction for deprotection and/or functional groupmodification in this step. Various well-known methods can be used forthe reaction. For the reaction of deprotection and functional groupmodification, for example, methods described in “Protective Groups inOrganic Syntheses”, (USA), Theodra W. Green, Peter G. M. Wuts, Eds.,Third edition, April in 1999, John Wiley & Sons, and “Handbook ofReagents for Organic Synthesis”, (USA), 4 Volumes, June in 1999, JohnWiley & Sons can be used, and for the reaction of functional groupmodification, for example, methods described in “Palladium Reagents inOrganic Syntheses”, (USA), Richard F. Heck, 1985, Academic Press, and“Palladium Reagents and Catalysts: Innovations in Organic Synthesis”,(USA), J. Tsuji, 1999, John Wiley & Sons, or the like can be used.

The compounds represented by the general formula (I) prepared by theaforementioned methods can be isolated and purified by methods widelyknown by those skilled in the art, for example, extraction,precipitation, fractional chromatography, fractional crystallization,suspension and washing, and recrystallization. Furthermore, each of thepharmaceutically acceptable salt of the compound of the presentinvention, the hydrate thereof and the solvate thereof can be preparedby methods widely known by those skilled in the art.

In the examples of the specification, preparation methods of typicalcompounds included in the general formula (I) are explained in details.Therefore, those skilled in the art can prepare any compound fall withinthe general formula (I) by referring to the explanations of theaforementioned general preparation methods and those of specificpreparation methods of the examples, by choosing appropriate reactionraw materials, reaction reagents, and reaction conditions, and by addingappropriate modification and alteration of these methods, if necessary.

The compounds represented by the general formula (I) have anticanceraction, therefore, the medicament comprising said compounds as activeingredients can be used for preventive and/or therapeutic treatment ofcancers. In the present specification, “the prevention and/or treatmentof cancers” or their synonyms should be interpreted in a broadest senseincluding inhibitory action against cancerous transformation of tissueor cells, inhibitory action against metastasis of cancer, enhancement ofexisting anticancer agents, action for overcoming drug tolerances ofexisting anticancer agents, action for improvement of cancerouscachexia, preventive action against recurrence, action for prolonginglifetime of cancer patients or the like, as well as actions of killingcancer cells or suppressing cancers, and should not be interpreted anylimitative sense. The medicament of the present invention may be usedfor preventive and/or therapeutic treatment of skin cancer, melanoma,kidney cancer, lung cancer, liver cancer, breast cancer, uterine cancer,pancreatic cancer, other solid cancer, sarcoma, osteosarcoma, metastaticinvasion of cancer, canceration of inflammatory focus, cancerouscachexia, metastasis of cancer, leukemia such as acute myeloblasticleukemia, multiple myeloma, Lennert's lymphoma, malignant lymphoma,development of carcinostatic resistance of cancer, canceration of focisuch as viral hepatitis and cirrhosis, canceration from polyp of colon,brain tumor, nervous tumor, sarcoidosis or the like. However, disease tobe applicable by the medicaments of the present invention are notlimited to these cancers.

As the active ingredient of the medicament on the present invention, oneor more kinds of substances selected from the group consisting of thecompound represented by the general formula (I) and a pharmacologicallyacceptable salt thereof, and a hydrate thereof and a solvate thereof maybe used. The aforementioned substance, per se, may be administered asthe medicament of the present invention, however, preferably, themedicament of the present invention is provided in the form of apharmaceutical composition comprising the aforementioned substance whichis an active ingredient together with one or more pharmacologicallyacceptable pharmaceutical additives. In the aforementionedpharmaceutical compositions, a ratio of the active ingredient to thepharmaceutical additives is 1 weight % to 90 weight %.

The pharmaceutical compositions of the present invention may beadministered as pharmaceutical compositions for oral administration, forexample, granules, subtilized granules, powders, hard capsules, softcapsules, syrup, emulsion, suspension, or solution, or may beadministered as pharmaceutical compositions for parenteraladministration, for example, injections for intravenous administration,intramuscular administration, or subcutaneous administration, dripinfusions, suppositories, percutaneous absorbent, transmucosalabsorption preparations, nasal drops, ear drops, instillation, andinhalants. Preparations made as pharmaceutical compositions in a form ofpowder may be dissolved when necessary and used as injections or dripinfusions.

For preparation of pharmaceutical compositions, solid or liquidpharmaceutical additives may be used. Pharmaceutical additives mayeither be organic or inorganic. When an oral solid preparation isprepared, an excipient is added to the active ingredient, and furtherbinders, disintegrator, lubricant, colorant, corrigent are added, ifnecessary, to manufacture preparations in the forms of tablets, coatingtablets, granules, powders, capsules and the like by ordinaryprocedures. Examples of the excipient include lactose, sucrose,saccharose, glucose, corn starch, starch, talc, sorbit, crystalcellulose, dextrin, kaolin, calcium carbonate, and silicon dioxide.Examples of the binder include, for example, polyvinyl alcohol,polyvinyl ether, ethyl cellulose, methyl cellulose, gum Arabic,tragacanth, gelatine, shellac, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, calcium citrate, dextrin, and pectin. Examples of thelubricant include, for example, magnesium stearate, talc, polyethyleneglycol, silica, and hydrogenated vegetable oil. As the coloring agent,any material can be used which are approved to be added to ordinarypharmaceuticals. As the corrigent, cocoa powder, menthol, aromatic acid,peppermint oil, d-borneol, cinnamon powder and the like can be used.These tables and granules may be applied with sugarcoating, gelatincoating, or an appropriate coating, if necessary. Preservatives,antioxidant and the like may be added, if required.

For liquid preparations for oral administration such as emulsions,syrups, suspensions, and solutions, ordinary used inactive diluents, forexample, water or vegetable oil may be used. For these preparations,besides inactive diluents, adjuvants such as wetting agents, suspendingaids, sweating agents, flavoring agents, coloring agents orpreservatives may be blended. After a liquid preparation ismanufactured, the preparation may be filled in capsules made of aabsorbable substance such as gelatin. Examples of solvents or suspendingagents used for the preparations of parenteral administration such asinjections or suppositories include, for example, water, propyleneglycol, polyethylene glycol, benzyl alcohol, ethyl oleate, and lecithin.Examples of base materials used for preparation of suppositoriesinclude, for example, cacao butter, emulsified cacao butter, lauric fat,and witepsol. Methods for preparation of the aforementioned preparationsare not limited, and any method ordinarily used in the art may be used.

When the composition are prepared in the form of injections, carrierssuch as, for example, diluents including water, ethanol, macrogol,propylene glycol, citric acid, acetic acid, phosphoric acid, lacticacid, sodium lactate, sulfuric acid and sodium hydroxide, pH modifiersand buffer solutions including sodium citrate, sodium acetate and sodiumphosphate, stabilizers such as sodium pyrosulfite,ethylenediaminetetraacetic acid, thioglycolic acid and thiolactate maybe used. For the preparation, a sufficient amount of a salt, glucose,mannitol or glycerin may be blended in the preparation to manufacture anisotonic solution, and an ordinary solubilizer, a soothing agent, or atopical anesthetic may be used.

When the preparation in the form of an ointment such as a paste, acream, and a gel is manufactured, an ordinarily used base material, astabilizer, a wetting agent, and a preservative may be blended, ifnecessary, and may be prepared by mixing the components by a commonmethod. As the base material, for example, white petrolatum,polyethylene, paraffin, glycerin, cellulose derivatives, polyethyleneglycol, silicon, and bentonite may be used. As the preservative, paraoxymethyl benzoate, paraoxy ethyl benzoate, paraoxy propyl benzoate and thelike may be used. When the preparation in the form of a patch ismanufactured, the aforementioned ointment, cream gel, or paste and thelike may be applied by a common method to an ordinary support. As thesupport, fabric made of cotton, span rayon, and synthetic fibersor ornonwoven fabric, and a film or a foam sheet such as made of soft vinylchloride, polyethylene, and polyurethane and the like may be preferablyused.

A dose of the medicament of the present invention is not particularlylimited. For oral administration, a dose may generally be 0.01 to 5,000mg per day for an adult as the weight of the compound of the presentinvention. It is preferred to increase or decrease the above doseappropriately depending on the age, pathological conditions, andsymptoms of a patient. The above dose may be administered once a day or2 to 3 times a day as divided portions with appropriate intervals, orintermittent administration for every several days may be applied. Whenthe medicament is used as an injection, the dose may be 0.001 to 100 mgper day for an adult as the weight of the compound of the presentinvention.

EXAMPLES

The present invention will be explained more specifically with referenceto the following examples. However the scope of the present invention isnot limited to the following examples. The compound number in thefollowing examples correspond to those in the table shown above. And thecommercially available compounds, which were purchased and used for theexaminations, are contained in these examples. As for such compounds,the suppliers of the reagents and the catalog code numbers are shown.

Example 1 Preparation of the Compound of Compound No. 1

3,5-Bis(trifluoromethyl)aniline (500 mg, 2.2 mmol) and pyridine (0.5 mL)were added to a solution of O-acetylsalicyloyl chloride (345 mg, 1.7mmol) in benzene (10 mL) under argon atmosphere, and the mixture wasstirred at room temperature for 1 hour. The reaction mixture was pouredinto 2N hydrochloric acid and extracted with ethyl acetate. After theethyl acetate layer was washed successively with water and brine, driedover anhydrous sodium sulfate, the residue obtained by evaporation ofthe solvent under reduced pressure was purified by column chromatographyon silica gel (n-hexane:ethyl acetate=3:1) to give the title compound(570 mg, 84.2%) as a white solid.

mp 124-125° C.

¹H-NMR(DMSO-d₆): δ 2.36(3H, s), 7.19(1H, dd, J=8.0, 1.2 Hz), 7.39(1H,td, J=7.6, 1.2 Hz), 7.57(1H, ddd, J=8.0, 7.6, 1.6 Hz), 7.65(1H, s),7.83(1H, dd, J=8.0, 1.6 Hz), 8.11(2H, s), 8.31(1H, s).

Example 2 Preparation of the Compound of Compound No. 2

2N Aqueous sodium hydroxide (0.5 mL, 1 mmol) was added to a solution of2-acetoxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide (Compound No. 1;100 mg, 0.25 mmol) in ethanol (5 mL), and the mixture was stirred atroom temperature for 1 hour. The reaction mixture was poured into 2Nhydrochloric acid and extracted with ethyl acetate. After the ethylacetate layer was washed successively with water and brine, dried overanhydrous sodium sulfate, the residue obtained by evaporation of thesolvent under reduced pressure was recrystallized from n-hexane/ethylacetate to give the title compound (40 mg, 45.1%) as a white solid.

mp 179-180° C.

¹H-NMR(DMSO-d₆): δ 6.96-7.02(2H, m), 7.45(1H, ddd, J=8.0, 7.2, 1.6 Hz),7.81(1H, s), 7.87(1H, dd, J=8.0, 1.6 Hz), 8.46(2H, s), 10.80(1H, s),11.26(1H, s).

Example 3 Preparation of the Compound of Compound No. 3

A mixture of 5-fluorosalicylic acid (156 mg, 1 mmol),3,5-bis(trifluoromethyl)aniline (229 mg, 1 mmol), phosphorus trichloride(44 μL, 0.5 mmol) and monochlorobenzene (5 mL) was refluxed for 3 hoursunder argon atmosphere. After the reaction mixture was cooled to roomtemperature, it was diluted with ethyl acetate (50 mL). After the ethylacetate layer was washed successively with water and brine, dried overanhydrous sodium sulfate, the residue obtained by evaporation of thesolvent under reduced pressure was purified by column chromatography onsilica gel (n-hexane:ethyl acetate=6:1) to give the title compound (215mg, 58.7%) as a white solid.

¹H-NMR(DMSO-d₆): δ 7.04(1H, ddd, J=9.0, 4.5, 1.2 Hz), 7.30-7.37(1H, m),7.66(1H, ddd, J=9.0, 3.3, 1.2 Hz), 7.84(1H, s), 8.46(2H, s), 10.85(1H,s), 11.21(1H, brs).

When the method described in Example 3 is referred in the followingexamples, phosphorus trichloride was used as the acid halogenatingagent. As the reaction solvent, solvents such as monochlorobenzene,toluene or the like were used.

Example 4 Preparation of the Compound of Compound No. 4

Using 5-chlorosalicylic acid and 3,5-bis(trifluoromethyl)aniline as theraw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 85.5%.

¹H-NMR(DMSO-d₆): δ 7.05(1H, d, J=8.7 Hz), 7.49(1H, dd, J=8.7, 2.7 Hz),7.85(1H, s), 7.87(1H, d, J=2.7 Hz), 8.45(2H, s), 10.85(1H, s), 11.39(1H,s).

Example 5 Preparation of the Compound of Compound No. 5

Acetyl chloride (234 mg, 3.3 mmol) was added to a solution ofN-[3,5-bis(trifluoromethylphenyl)]-5-chloro-2-hydroxybenzamide (CompoundNo. 4; 1.51 g, 3 mmol) and pyridine (285 mg, 3.6 mmol) intetrahydrofuran (6 mL) under ice cooling, and the mixture was stirred atroom temperature for 1 hour. 2N Hydrochloric acid was added to theresidue obtained by evaporation of the solvent under reduced pressureand the mixture was extracted with ethyl acetate. After the ethylacetate layer was washed successively with water and brine, dried overanhydrous magnesium sulfate, the residue obtained by evaporation of thesolvent under reduced pressure was recrystallized from n-hexane/ethylacetate to give the title compound 1.06 g, 83.0%) as a white solid.

¹H-NMR(DMSO-d₆): δ 2.22(3H, s), 7.35(1H, d, J=9.0 Hz), 7.71(1H, dd,J=8.7, 2.7 Hz), 7.85(1H, s), 7.88(1H, d, J=2.7 Hz), 8.37(2H, s),11.05(1H, brs).

When the method described in Example 5 is referred in the followingexamples, organic bases such as pyridine, triethylamine or the like wereused as the base. As the reaction solvent, solvents such asdichloromethane, tetrahydrofuran, benzene or the like were used.

Example 6 Preparation of the Compound of Compound No. 6

Using 5-bromosalicylic acid and 3,5-bis(trifluoromethyl)aniline as theraw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 88.5%.

¹H-NMR(DMSO-d₆): δ 6.98(1H, d, J=8.8 Hz), 7.59(1H, dd, J=8.8, 2.8 Hz),7.83(1H, s), 7.98(1H, d, J=2.8 Hz), 8.43(2H, s), 10.82(1H, s), 11.37(1H,s).

This compound was obtained also by the following preparation method.

Iron powder (30 mg, 0.54 mmol) and bromine (0.02 mL, 0.39 mmol) wereadded to a solution of 2-acetoxy-N-[3,5-bis(trifluoromethyl)]benzamide(Compound No. 1; 100 mg, 0.25 mmol) in carbon tetrachloride (8 mL), andthe mixture was stirred at 50° C. for 4 hours. After the reactionmixture was cooled to room temperature, it was poured into aqueousNaHSO₄ and extracted with ethyl acetate. The ethyl acetate layer waswashed with water and brine, and dried over anhydrous sodium sulfate.The residue obtained by evaporation of the solvent under reducedpressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=4:1) to give the title compound (600 mg, 54.9%)as a white solid.

Example 7 Preparation of the Compound of Compound No. 7

Using 5-iodosalicylic acid and 3,5-bis(trifluoromethyl)aniline as theraw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 62.2%.

¹H-NMR(DMSO-d₆): δ 6.86(1H, d, J=8.4 Hz), 7.74(1H, dd, J=8.7, 2.4 Hz),7.84(1H, s), 8.13(1H, d, J=2.1 Hz), 8.84(2H, s), 10.82(1H, s), 11.41(1H,s).

Example 8 Preparation of the Compound of Compound No. 8

Using 5-nitrosalicylic acid and 3,5-bis(trifluoromethyl)aniline as theraw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 57.2%.

¹H-NMR(DMSO-d₆): δ 7.18(1H, d, J=9.0 Hz), 7.86(1H, s), 8.31(1H, dd,J=9.0, 3.0 Hz), 8.45(2H, s), 8.70(1H, d, J=3.0 Hz), 11.12(1H, s).

Example 9 Preparation of the Compound of Compound No. 9 (1)2-Benzyloxy-5-formylbenzoic acid benzyl ester

A mixture of 5-formylsalicylic acid (4.98 g, 30 mmol), benzyl bromide(15.39 g, 90 mmol), potassium carbonate (16.59 g, 120 mmol), and methylethyl ketone (350 mL) was refluxed for 8 hours. After cooling, thesolvent was evaporated under reduced pressure. 2N Hydrochloric acid wasadded to the residue, and the mixture was extracted with ethyl acetate.The layer was washed with water and brine, and dried over anhydrousmagnesium sulfate. The residue obtained by evaporation of the solventunder reduced pressure was purified by column chromatography on silicagel (n-hexane:ethyl acetate=3:1), suspended and washed with isopropylether under heating at reflux to give the title compound (5.98 g, 57.5%)as a white solid.

¹H-NMR(CDCl₃): δ 5.27(2H, s), 5.37(2H, s), 7.15(1H, d, J=9.0 Hz),7.26-7.46(10H, m), 7.99(1H, dd, J=9.0, 2.4 Hz), 8.36(1H, d, J=2.4 Hz),9.91(1H, s).

(2) 2-Benzyloxy-5-cyanobenzoic acid benzyl ester

A mixture of 2-benzyloxy-5-formylbenzoic acid benzyl ester (693 mg, 2mmol), hydroxylamine hydrochloride (167 mg, 2.4 mmol), andN-methylpyrrolidone (3 mL) was stirred at 115□for 4 hours. After thereaction mixture was cooled, 2N hydrochloric acid (5 mL) and water (30mL) were added and the mixture was extracted with ethyl acetate. Theorganic layer was washed with 2N aqueous sodium hydroxide, water, andbrine, and dried over anhydrous magnesium sulfate. The residue obtainedby evaporation of the solvent under reduced pressure was suspended andwashed with isopropyl ether under heating at reflux to give the titlecompound (527 mg, 76.7%) as a white solid.

¹H-NMR(CDCl₃): δ 5.23(2H, s), 5.35(2H, s), 7.08(1H, d, J=8.7 Hz),7.33-7, 43(10H, m), 7.70(1H, dd, J=8.7, 2.4 Hz), 8.13(1H, d, J=2.4 Hz).

(3) 5-Cyanosalicylic acid

Ethanol (10 mL) and tetrahydrofuran (10 mL) were added to2-benzyloxy-5-cyanobenzoic acid benzyl ester (446 mg, 1.3 mmol) and 5%palladium on carbon (45 mg), and the mixture was hydrogenated at roomtemperature for 2 hours. After the insoluble matter was filtered off,the solvent was evaporated under reduced pressure to give the titlecompound (212 mg, 100.0%) as a white solid.

¹H-NMR(DMSO-d₆): δ 7.02(1H, d, J=8.7 Hz), 7.82(1H, dd, J=8.7, 2.4 Hz),8.12(1H, d, J=2.1 Hz).

(4) N-[3,5-Bis(trifluoromethyl)phenyl]-5-cyano-2-hydroxybenzamide(Compound No. 9)

Using 5-cyanosalicylic acid and 3,5-bis(trifluoromethyl)aniline as theraw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 16.6%.

¹H-NMR(DMSO-d₆): δ 7.15(1H, d, J=8.7 Hz), 7.85(1H, s), 7.86(1H, dd,J=8.7, 2.1 Hz), 8.22(1H, d, J=2.4 Hz), 8.43(2H, s), 10.93(1H, s),12.00(1H, brs).

Example 10 Preparation of the Compound of Compound No. 10

Using 5-methylsalicylic acid and 3,5-bis(trifluoromethyl)aniline as theraw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 54.9%.

¹H-NMR(DMSO-d₆): δ 6.92(1H, d, J=8.7 Hz), 7.28(1H, dd, J=8.7, 1.8 Hz),7.71(1H, d, J=1.8 Hz), 7.82(1H, s), 8.47(2H, s), 10.80(1H, s), 11.14(1H,s).

Example 11 Preparation of the Compound of Compound No. 11 (1)5-[(1,1-Dimethyl)ethyl]salicylic acid

Sulfamic acid (1.76 g, 18.1 mmol) and sodium dihydrogenphosphate (7.33g, 47 mmol) were added to a solution of5-[(1,1-dimethyl)ethyl]-2-hydroxybenzaldehyde (2.15 g, 12.1 mmol) in1,4-dioxane (100 mL) and water (40 mL). A solution of sodium chlorite(1.76 g, 15.5 mmol) in water (10 mL) was added to the mixture under icecooling, and it was stirred for 1 hour. Then, sodium sulfite (1.80 g,14.3 mmol) was added to the mixture, and it was stirred for 30 minutes.Concentrated hydrochloric acid was added to the reaction mixture, and pHwas adjusted to 1. The residue obtained by evaporation of 1,4-dioxaneunder reduced pressure was extracted with ethyl acetate. The organiclayer was washed with water and brine, and dried over anhydrousmagnesium sulfate. The residue obtained by evaporation of the solventunder reduced pressure was washed with n-hexane under suspension to givethe title compound (1.81 g, 77.4%) as a white powder.

¹H-NMR(DMSO-d₆): δ 1.26(9H, s), 6.90(1H, d, J=9.0 Hz), 7.58(1H, dd,J=8.7, 2.4 Hz), 7.75(1H, d, J=2.4 Hz), 11.07(1H, brs).

(2)N-[3,5-Bis(trifluoromethyl)phenyl]-5-[(1,1-dimethyl)ethyl]-2-hydroxybenzamide(Compound No. 11)

Using 5-[(1,1-dimethyl)ethyl]salicylic acid and3,5-bis(trifluoromethyl)aniline as the raw materials, the same operationas the Example 3 gave the title compound.

Yield: 53.8%.

¹H-NMR(DMSO-d₆): δ 1.30(9H, s), 6.96(1H, d, J=8.7 Hz), 7.50(1H, dd,J=8.7, 2.4 Hz), 7.82(1H, d, J=2.4 Hz), 7.83(1H, s), 8.46(2H, s),10.80(1H, s) 11.12(1H, s).

Example 12 Preparation of the Compound of Compound No. 12 (1)5-Acetyl-2-benzyloxybenzoic acid methyl ester

A mixture of 5-acetylsalicylic acid methyl ester (13.59 g, 70 mmol),benzyl bromide (17.96 g, 105 mmol), potassium carbonate (19.35 g, 140mmol) and methyl ethyl ketone (350 mL) was refluxed for 8 hours. Aftercooling, the solvent was evaporated under reduced pressure. 2NHydrochloric acid was added to the residue, and it was extracted withethyl acetate. After the ethyl acetate layer was washed with water andbrine, dried over anhydrous magnesium sulfate and concentrated, theresidue was recrystallized from isopropyl ether to give the titlecompound (14.20 g, 71.4%) as a white solid.

¹H-NMR(CDCl₃): δ 2.58(3H, s), 3.93(3H, s), 5.27(2H, s), 7.07(1H, d,J=8.7 Hz), 7.26-7.43(3H, m), 7.47-7.50(2H, m), 8.07(1H, dd, J=8.7, 2.4Hz), 8.44(1H, d, J=2.4 Hz).

(2) 5-Acetyl-2-benzyloxybenzoic acid

2N Sodium hydroxide (11 mL) was added to a solution of5-acetyl-2-benzyloxybenzoic acid methyl ester (5.69 g, 20 mmol) in amixed solvent of methanol/tetrahydrofuran (20 mL+20 mL), and the mixturewas stirred for 8 hours. 2N Hydrochloric acid was added to the residueobtained by evaporation of the solvent under reduced pressure and themixture was extracted with dichloromethane. After the dichloromethanelayer was washed successively with water and brine, dried over anhydrousmagnesium sulfate, the residue obtained by evaporation of the solventunder reduced pressure was washed with isopropyl ether to give the titlecompound (4.92 g, 91.0%) as a white solid.

¹H-NMR(DMSO-d₆): δ 2.55(3H, s), 5.32(2H, s), 7.30-7.43(4H, m),7.49-7.52(2H, m), 8.09(1H, dd, J=9.0, 2.7 Hz), 8.22(1H, d, J=2.4 Hz).

(3) 5-Acetyl-2-benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide

Phosphorus oxychloride 1.85 mL, 19.8 mmol) was added to a solution of5-acetyl-2-benzyloxybenzoic acid (4.87 g, 18 mmol),3,5-bis(trifluoromethyl)aniline (4.54 g, 19.8 mmol) and pyridine (5.70g, 72 mmol) in a mixed solvent of tetrahydrofuran/dichloromethane (72mL+36 mL) under ice cooling, and the mixture was stirred at roomtemperature for 12 hours. 1N Hydrochloric acid (100 mL) was added to theresidue obtained by evaporation of the solvent under reduced pressureand the mixture was extracted with ethyl acetate. After the ethylacetate layer was washed successively with water and brine, dried overanhydrous magnesium sulfate, the residue obtained by evaporation of thesolvent under reduced pressure was purified by column chromatography onsilica gel (n-hexane:ethyl acetate=3:1→2:1) to give the title compound(5.47 g, 63.1%) as a slightly yellowish green crystal.

¹H-NMR(DMSO-d₆): δ 2.57(3H, s), 7.11(1H, d, J=8.7 Hz), 7.86(1H, s),8.05(1H, dd, J=8.4, 2.1 Hz), 8.44(1H, d, J=2.1 Hz), 8.47(2H, s),10.96(1H, s), 11.97(1H, brs).

When the preparation method described in Example 12(3) is referred inthe following examples, phosphorus oxychloride was used as the acidhalogenating agent. Pyridine was used as the base. As the reactionsolvent, solvents such as dichloromethane, tetrahydrofuran or the likewere used alone or as a mixture.

(4) 5-Acetyl-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide(Compound No. 12)

Ethanol (6 mL) and tetrahydrofuran (72 mL) were added to5-acetyl-2-benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide (602mg, 1.25 mmol) and 5% palladium on carbon (60 mg), and the mixture wasstirrred at room temperature for 30 minutes under hydrogen atmosphere.After the insoluble matter was filtered off, the residue obtained byevaporation of the solvent under reduced pressure was recrystallizedfrom n-hexane/ethyl acetate to give the title compound (230 mg, 47.0%)as a white solid.

¹H-NMR(DMSO-d₆): δ 2.59(3H, s), 5.35(2H, s), 7.32-7.36(3H, m), 7.43(1H,d, J=8.7 Hz), 7.52-7.55(2H, m), 7.82(1H, s), 8.16(1H, dd, J=8.7, 2.4Hz), 8.25(1H, d, J=2.4 Hz), 8.31(2H, s), 10.89(1H, s).

Example 13 Preparation of the Compound of Compound No. 13

Sodium borohydride (23.6 mg, 0.62 mmol) was added to a suspension of5-acetyl-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide (CompoundNo. 12; 50.5 mg, 0.13 mmol) in ethanol (2 mL), and the mixture wasstirred at room temperature for 12 hours. The reaction mixture waspoured into diluted hydrochloric acid and extracted with ethyl acetate.After the ethyl acetate layer was washed with water and brine, driedover anhydrous sodium sulfate, the residue obtained by evaporation ofthe solvent under reduced pressure was washed with isopropylether/n-hexane under suspension to give the title compound (39.7 mg,78.3%) as a white powder.

¹H-NMR(DMSO-d₆): δ 1.34(3H, d, J=6.3 Hz), 4.71(1H, q, J=6.3 Hz),5.18(1H, brs), 6.97(1H, d, J=8.4 Hz), 7.44(1H, dd, J=8.4, 2.1 Hz),7.84(1H, s), 7.86(1H, d, J=2.1 Hz), 8.48(2H, s), 10.85(1H, s), 11.32(1H,s).

Example 14 Preparation of the Compound of Compound No. 14

Pyridine (45 μL, 0.56 mmol) and O-methylhydroxylamine hydrochloride(25.8 mg, 0.31 mmol) were added to a solution of5-acetyl-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide (CompoundNo. 12; 100.0 mg, 0.26 mmol) in ethanol (3 mL), and the mixture wasrefluxed for 1 hour. After the reaction mixture was cooled to roomtemperature, it was poured into diluted hydrochloric acid and extractedwith ethyl acetate. After the ethyl acetate layer was washed with waterand brine, dried over anhydrous sodium sulfate, the residue obtained byevaporation of the solvent under reduced pressure was purified by columnchromatography on silica gel (n-hexane:ethyl acetate=4:1) to give thetitle compound (102.1 mg, 95.3%) as a white crystal.

¹H-NMR(DMSO-d₆): δ 2.19(3H, s), 3.91(3H, s), 7.05(1H, d, J=8.7 Hz),7.77(1H, dd, J=8.7, 2.4 Hz), 7.85(1H, s), 8.09(1H, d, J=2.4 Hz),8.47(2H, s), 10.87(1H, s), 11.48(1H, s).

Example 15 Preparation of the Compound of Compound No. 15

Using 5-acetyl-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide(Compound No. 12) and O-benzylhydroxylamine hydrochloride as the rawmaterials, the same operation as the Example 14 gave the title compound.

Yield: 79.9%.

¹H-NMR(DMSO-d₆): δ 2.24(3H, s), 5.20(2H, s), 7.04(1H, d, J=8.7 Hz),7.29-7.47(5H, m), 7.76(1H, dd, J=8.7, 2.4 Hz), 7.85(1H, s), 8.07(1H, d,J=2.1 Hz), 8.46(2H, s), 10.87(1H, s), 11.47(1H, s).

Example 16 Preparation of the Compound of Compound No. 16 (1)5-(2,2-Dicyanoethen-1-yl)-2-hydroxybenzoic acid

5-Formylsalicylic acid (332 mg, 2 mmol) was added to a solution ofmalononitrile (132 mg, 2 mmol) in ethanol (6 mL). Benzylamine (0.1 mL)was added under ice cooling and the mixture was stirred at roomtemperature for 2 hours. The separated yellow crystal was filtered andrecrystallized from ethanol to give the title compound (139.9 mg, 32.7%)as a light yellow solid.

¹H-NMR(DMSO-d₆): δ 7.12(1H, d, J=8.7 Hz), 8.09(1H, dd, J=8.7, 2.4 Hz),8.41(1H, s), 8.50(1H, d, J=2.4 Hz).

(2)N-[3,5-Bis(trifluoromethyl)phenyl]-5-(2,2-dicyanoethen-1-yl)-2-hydroxybenzamide(Compound No. 16)

Using 5-(2,2-dicyanoethen-1-yl)-2-hydroxybenzoic acid and3,5-bis(trifluoromethyl)aniline as the raw materials, the same operationas the Example 3 gave the title compound.

Yield: 9.1%.

¹H-NMR(DMSO-d₆): δ 7.13(1H, d, J=9.0 Hz), 7.83(1H, s), 8.04(1H, dd,J=9.0, 2.4 Hz), 8.36(1H, s), 8.38(1H, d, J=2.4 Hz), 8.43(2H, s),11.43(1H, s).

Example 17 Preparation of the Compound of Compound No. 17 (1)5-[(2-Cyano-2-methoxycarbonyl)ethen-1-yl]-2-hydroxybenzoic acid

A mixture of 5-formylsalicylic acid (332 mg, 2 mmol), Cyanoacetic acidmethyl ester (198 mg, 2 mmol), acetic acid (6 mL) and triethylamine (0.2ml) was refluxed for 5 hours. After the reaction mixture was cooled toroom temperature, it was poured into water, and the separated crystalwas filtered and recrystallized from n-hexane to give the title compound(327.7 mg, 66.3%) as a light yellow solid.

¹H-NMR(DMSO-d₆): δ 3.85(3H, s), 7.15(1H, d, J=8.7 Hz), 8.20(1H, dd,J=8.7, 2.4 Hz), 8.37(1H, s), 8.66(1H, d, J=2.4 Hz).

(2)3-({N-[3,5-Bis(trifluoromethyl)phenyl]carbamoyl}-4-hydroxyphenyl)-2-cyanoacrylicacid methyl ester (Compound No. 17)

Using 5-[(2-cyano-2-methoxycarbonyl)ethen-1-yl]-2-hydroxybenzoic acidand 3,5-bis(trifluoromethyl)aniline as the raw materials, the sameoperation as the Example 3 gave the title compound.

Yield: 66.3%.

¹H-NMR(DMSO-d₆): δ 3.85(3H, s), 7.19(1H, d, J=9.0 Hz), 7.85(1H, s),8.20(1H, dd, J=8.7, 2.1 Hz), 8.33(1H, s), 8.45(2H, s), 8.50(1H, d, J=2.1Hz), 11.00(1H, s), 11.03(1H, s).

Example 18 Preparation of the Compound of Compound No. 18

2N Sodium hydroxide (0.11 ml, 0.22 mmol) was added to a solution of3-({N-[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-hydroxyphenyl)-2-cyanoacrylicacid methyl ester (Compound No. 17; 50 mg, 0.11 mmol) in ethanol (5 mL),and the mixture was stirred at room temperature for 3 hours. Thereaction mixture was poured into diluted hydrochloric acid and extractedwith ethyl acetate. After the organic layer was washed with brine, driedover anhydrous magnesium sulfate, the residue obtained by evaporation ofthe solvent under reduced pressure was recrystallized from ethyl acetateto give the title compound (13.5 mg, 30.4%) as a light yellow solid.

¹H-NMR(DMSO-d₆): δ 7.12(1H, d, J=8.4 Hz), 7.84(1H, s), 7.94(1H, dd,J=8.4, 2.1 Hz), 8.38(1H, d, J=2.1 Hz), 8.45(2H, s), 9.87(1H, s),11.41(1H, s).

Example 19 Preparation of the Compound of Compound No. 19

A mixture ofN-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide (CompoundNo. 7; 475 mg, 1 mmol), styrene (130 mg, 1.25 mmol), palladium acetate(4.5 mg, 0.02 mmol), tris(ortho-tolyl)phosphine (12.2 mg, 0.04 mmol),diisopropylamine (388 mg, 3 mmol) and N,N-dimethylformamide (2 mL) wasrefluxed for 8 hours. After the reaction mixture was cooled to roomtemperature, water was added and the mixture was extracted with ethylacetate. After the ethyl acetate layer was washed successively withwater and brine, dried over anhydrous magnesium sulfate, the residueobtained by evaporation of the solvent under reduced pressure waspurified by column chromatography on silica gel (n-hexane:isopropylether=2:1→1:1) to give the title compound (173 mg, 38.3%) as a paleyellow solid.

¹H-NMR(DMSO-d₆): δ 7.04(1H, d, J=8.4 Hz), 7.20-7.29(3H, m), 7.38(2H, t,J=7.5 Hz), 7.59(2H, d, J=7.5 Hz), 7.72(1H, dd, J=8.4, 2.1 Hz), 7.86(1H,s), 8.07(1H, d, J=2.1 Hz), 8.49(2H, s), 10.89(1H, s), 11.33(1H, brs).

Example 20 Preparation of the Compound of Compound No. 20

Tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol) and cuprousiodide (4 mg, 0.02 mmol) were added to a solution ofN-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide (CompoundNo. 7; 950 mg, 2 mmol), trimethylsilylacetylene (246 mg, 2.5 mmol) andtriethylamine (2 mL) in N,N-dimethylformamide (4 mL) under argonatmosphere, and the mixture was stirred at 40° C. for 2 hours. After thereaction mixture was cooled to room temperature, it was poured intoethyl acetate (100 mL) and 1N citric acid (100 mL), stirred, andfiltered through celite. After the ethyl acetate layer was washedsuccessively with water and brine, dried over anhydrous magnesiumsulfate, the residue obtained by evaporation of the solvent underreduced pressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=19:1) and crystallized by n-hexane to give thetitle compound (286 mg, 32.1%) as a white crystal.

¹H-NMR(DMSO-d₆): δ 0.23(9H, s), 7.00(1H, d, J=8.7 Hz), 7.54(1H, dd,J=8.7, 2.4 Hz), 7.85(1H, s), 7.98(1H, d, J=2.1 Hz), 8.46(2H, s),10.86(1H, s), 11.69(1H, s).

Example 21 Preparation of the Compound of Compound No. 21

2N Sodium hydroxide (1 mL) was added to a solution ofN-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-[(trimethylsilyl)ethynyl]benzamide(Compound No. 20; 233 mg, 0.5 mmol) in methanol (1 mL), and the mixturewas stirred at room temperature for 1 hour. The reaction mixture waspoured into 2N hydrochloric acid and extracted with ethyl acetate. Afterthe ethyl acetate layer was washed successively with water and brine,dried over anhydrous magnesium sulfate, the residue obtained byevaporation of the solvent under reduced pressure was recrystallizedfrom ethanol/water to give the title compound (67 mg, 35.9%) as a lightgray crystal.

¹H-NMR(DMSO-d₆): δ 4.11(1H, s), 7.02(1H, d, J=8.4 Hz), 7.55(1H, dd,J=8.4, 2.1 Hz), 7.85(1H, s), 7.98(1H, d, J=2.1 Hz), 8.46(2H, s),8.46(2H, s), 10.86(1H, s), 11.62(1H, s).

Example 22 Preparation of the Compound of Compound No. 22

Using N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide(Compound No. 7) and phenylacetylene as the raw materials, the sameoperation as the Example 20 gave the title compound.

Yield: 40.8%.

¹H-NMR(DMSO-d₆): δ 7.06(1H, d, J=8.4 Hz), 7.42-7.46(3H, m),7.53-7.57(2H, m), 7.64(1H, dd, J=8.7, 2.1 Hz), 7.86(1H, s), 8.06(1H, d,J=2.1 Hz), 8.48(2H, s), 10.94(1H, s), 11.64(1H, brs).

Example 23 Preparation of the Compound of Compound No. 23

Tetrakis(triphenylphosphine)palladium (16 mg, 0.0014 mmol) was added toa solution ofN-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide (CompoundNo. 7; 200 mg, 0.42 mmol) in 1,2-dimethoxyethane (3 mL) under argonatmosphere, and the mixture was stirred at room temperature for 5minutes. Then dihydroxyphenylborane (57 mg, 0.47 mmol) and 1 mol/Laqueous sodium carbonate (1.3 mL) were added and the mixture wasrefluxed for 2 hours. After the reaction mixture was cooled to roomtemperature, it was poured into diluted hydrochloric acid and extractedwith ethyl acetate. After the ethyl acetate layer was washedsuccessively with water and brine, dried over anhydrous sodium sulfate,the residue obtained by evaporation of the solvent under reducedpressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=6:1→3:1) to give the title compound (109 mg,61.1%) as a white crystal.

¹H-NMR(DMSO-d₆): δ 7.12(1H, d, J=8.7 Hz), 7.33-7.38(1H, m), 7.48(2H, t,J=7.5 Hz), 7.67-7.70(2H, m), 7.79(1H, dd, J=8.4, 2.4 Hz), 7.87(1H, s),8.17(1H, d, J=2.4 Hz), 8.49(2H, s), 10.92(1H, s), 11.41(1H, s).

Example 24 Preparation of the Compound of Compound No. 24

UsingN-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-(phenylethynyl)benzamide(Compound No. 22) as the raw material, the same operation as the Example12(4) gave the title compound.

Yield: 86.2%.

¹H-NMR(DMSO-d₆): δ 2.88(4H, s), 6.93(1H, d, J=8.1 Hz), 7.15-7.34(6H, m),7.76(1H, d, J=2.4 Hz), 7.84(1H, s), 8.47(2H, s), 10.79(1H, s), 11.15(1H,s).

Example 25 Preparation of the Compound of Compound No. 25

Using 2-hydroxy-5-(trifluoromethyl)benzoic acid and3,5-bis(trifluoromethyl)aniline as the raw materials, the same operationas the Example 3 gave the title compound.

Yield: 44.7%.

¹H-NMR(CDCl₃): δ 7.17(1H, d, J=9.0 Hz) 7.72-7.75(2H, m), 7.86(1H, s),8.17(2H, s), 8.35(1H, s) 11.88(1H, s).

-   [2-Hydroxy-5-(trifluoromethyl)benzoic acid: Refer to “Chemical and    Pharmaceutical Bulletin”, 1996, Vol. 44, No. 4, p. 734-745.]

Example 26 Preparation of the Compound of Compound No. 26

Using 2-hydroxy-5-(pentafluoroethyl)benzoic acid and3,5-bis(trifluoromethyl)aniline as the raw materials, the same operationas the Example 3 gave the title compound.

Yield: 65.7%.

¹H-NMR(CDCl₃): δ 7.19(1H, d, J=9.0 Hz) 7.70(1H, dd, J=8.7, 2.1 Hz),7.81(1H, d, J=2.1 Hz), 8.17(2H, s), 8.37(1H, s), 11.92(1H, s).

-   [2-Hydroxy-5-(pentafluoroethyl)benzoic acid: Refer to “Chemical and    Pharmaceutical Bulletin”, 1996, Vol. 44, No. 4, p. 734-745.]

Example 27 Preparation of the Compound of Compound No. 27

Using 2-hydroxy-5-(pyrrol-1-yl)benzoic acid and3,5-bis(trifluoromethyl)aniline as the raw materials, the same operationas the Example 3 gave the title compound.

Yield: 57.8%.

¹H-NMR(DMSO-d₆): δ 6.27(2H, dd, J=2.4, 1.8 Hz), 7.10(1H, d, J=9.0 Hz),7.29(2H, dd, J=2.4, 1.8 Hz), 7.66(1H, dd, J=9.0, 2.7 Hz), 7.86(1H, s),7.98(1H, d, J=2.4 Hz), 8.47(2H, s), 10.89(1H, s), 11.24(1H, s).

Example 28 Preparation of the Compound of Compound No. 28

Using N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide(Compound No. 7) and 2-thiopheneboronic acid as the raw materials, thesame operation as the Example 23 gave the title compound.

Yield: 44.4%.

¹H-NMR(DMSO-d₆): δ 7.08(1H, d, J=8.4 Hz), 7.14(1H, dd, J=5.4, 3.6 Hz),7.45(1H, dd, J=3.6, 1.2 Hz), 7.51(1H, dd, J=5.1, 0.9 Hz), 7.75(1H, dd,J=8.4, 2.4 Hz), 7.59(1H, s), 8.08(1H, d, J=2.4 Hz), 8.48(2H, s),10.91(1H, s), 11.38(1H, s).

Example 29 Preparation of the Compound of Compound No. 29

Using N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide(Compound No. 7) and 3-thiopheneboronic acid as the raw materials, thesame operation as the Example 23 gave the title compound.

Yield: 38.7%.

¹H-NMR(DMSO-d₆): δ 7.06(1H, d, J=8.7 Hz), 7.57(1H, dd, J=4.8, 1.5 Hz),7.66(1H, dd, J=4.8, 3.0 Hz), 7.81-7.84(2H, m), 7.86(1H, s), 8.18(1H, d,J=2.1 Hz), 8.49(2H, s), 10.90(1H, s), 11.33(1H, s).

Example 30 Preparation of the Compound of Compound No. 30 (1)2-Benzyloxy-5-(2-bromoacetyl)-N-[3,5-bis(trifluoromethyl)phenyl]benzamide

Phenyltrimethylammonium tribromide (3.75 g, 10 mmol) was added to asolution of5-acetyl-2-benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide(compound of Example 12(3); 4.81 g, 10 mmol) in tetrahydrofuran (30 ml),and the mixture was stirred at room temperature for 12 hours. Thereaction mixture was poured into water and extracted with ethyl acetate.After the ethyl acetate layer was washed successively with aqueoussodium hydrogen sulfite, water and brine, dried over anhydrous magnesiumsulfate, the residue obtained by evaporation of the solvent underreduced pressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=4:1), and recrystallized from ethylacetate/n-hexane to give the title compound (2.39 g, 42.7%) as a whitesolid.

¹H-NMR(DMSO-d₆): δ 4.91(2H, s), 5.36(2H, s), 7.32-7.35(3H, m), 7.47(1H,d, J=9.0 Hz), 7.52-7.56(2H, m), 7.82(1H, s), 8.21(1H, dd, J=8.7, 2.4Hz), 8.29(1H, d, J=2.4 Hz), 8.31(2H, s), 10.91(1H, s).

(2)2-Benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]-5-(2-methylthiazol-4-yl)benzamide

A mixture of2-benzyloxy-5-(2-bromoacetyl)-N-[3,5-bis(trifluoromethyl)phenyl]benzamide(280 mg, 0.5 mmol), thioacetamide (41 mg, 0.55 mmol), sodium hydrogencarbonate (50 mg, 0.6 mmol) and ethanol (15 mL) was refluxed for 1 hour.After the reaction mixture was cooled to room temperature, it was pouredinto water and extracted with ethyl acetate. After the ethyl acetatelayer was washed successively with water and brine, dried over anhydrousmagnesium sulfate, the residue obtained by evaporation of the solventunder reduced pressure was purified by column chromatography on silicagel (hexane:ethyl acetate=4:1) to give the title compound (181 mg,67.5%) as a white solid.

¹H-NMR(DMSO-d₆): δ 2.72(3H, s), 5.29(2H, s), 7.33-7.36(3H, m), 7.40(1H,d, J=9.0 Hz), 7.54-7.57(2H, m), 7.81(1H, s), 7.94(1H, s), 8.12(1H, dd,J=8.7, 2.1 Hz), 8.27(1H, d, J=2.1 Hz), 8.31(2H, s), 10.86(1H, s).

(3)N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-(2-methylthiazol-4-yl)benzamide(Compound No. 30)

Ethanol (10 ml) was added to2-benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]-5-(2-methylthiazol-4-yl)benzamide(160 mg, 0.3 mmol) and 10% palladium on carbon (240 mg), and the mixturewas stirred for 3.5 hours under hydrogen atmosphere. The reactionmixture was filtered and the solvent was evaporated under reducedpressure to give the title compound (103.4 mg, 79.2%) as a white solid.

¹H-NMR(DMSO-d₆): δ 2.72(3H, s), 7.08(1H, d, J=8.7 Hz), 7.83(1H, s),7.85(1H, s), 8.01(1H, dd, J=8.7, 2.4 Hz), 8.42(1H, d, J=2.1 Hz),8.50(2H, s), 10.96(1H, s), 11.40(1H, s).

Example 31 Preparation of the Compound of Compound No. 31

A mixture of2-benzyloxy-5-(2-bromoacetyl)-N-[3,5-bis(trifluoromethyl)phenyl]benzamide(compound of Example 12(3); 280 mg, 0.5 mmol), 2-aminopyridine (51.8 mg,0.55 mmol), sodium hydrogen carbonate (50 mg, 0.6 mmol) and ethanol (10mL) was refluxed for 2 hours. After the reaction mixture was cooled toroom temperature, it was poured into aqueous sodium hydrogen carbonateand extracted with ethyl acetate. After the ethyl acetate layer waswashed successively with water and brine, dried over anhydrous magnesiumsulfate, the residue obtained by evaporation of the solvent underreduced pressure was purified by column chromatography on silica gel(hexane:ethyl acetate=1:2) to give a white solid (130.3 mg, 45.9%).Then, a mixture of this solid (108 mg, 0.19 mmol), 10% palladium oncarbon (11 mg), ethanol (8 mL) and ethyl acetate (8 mL) was stirred for7 hours under hydrogen atmosphere. The reaction mixture was filtered andthe residue obtained by evaporation of the solvent under reduced pressurwas purified by column chromatography on silica gel (n-hexane:ethylacetate=1:3) to give the title compound (18.3 mg, 20.2%) as a whitesolid.

¹H-NMR(DMSO-d₆): δ 6.90(1H, dt, J=6.6, 0.9 Hz), 7.10(1H, d, J=8.7 Hz),7.25(1H, m), 7.57(1H, d, J=9.0 Hz), 7.86(1H, s), 8.04(1H, dd, J=8.7, 2.1Hz), 8.35(1H, s), 8.48-8.56(4H, m), 11.00(1H, s), 11.41(1H, s).

Example 32 Preparation of the Compound of Compound No. 32 (1)N-[3,5-Bis(trifluoromethyl)phenyl]-5-iodo-2-methoxymethoxybenzamide

A mixture ofN-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide (CompoundNo. 7; 4.75 g, 10 mmol), chloromethyl methyl ether (1.14 ml, 15 mmol),potassium carbonate (2.76 g, 20 mmol) and acetone (50 mL) was refluxedfor 8 hours. After the reaction mixture was cooled to room temperature,it was poured into diluted hydrochloric acid and extracted with ethylacetate. After the ethyl acetate layer was washed successively withwater and brine, dried over anhydrous magnesium sulfate, the residueobtained by evaporation of the solvent under reduced pressure waspurified by column chromatography on silica gel (hexane:ethylacetate=3:1) and recrystallized from n-hexane/ethyl acetate to give thetitle compound (3.96 g, 76.3%) as a white solid.

¹H-NMR(DMSO-d₆): δ 3.38(3H, s), 5.28(2H, s), 7.12(1H, d, J=9.0 Hz),7.81(1H, s), 7.82(1H, dd, J=8.7, 2.4 Hz), 7.88(1H, d, J=2.4 Hz),8.40(2H, s), 10.87(1H, s).

(2)N-[3,5-Bis(trifluoromethyl)phenyl]-2-methoxymethoxy-5-(pyridin-2-yl)benzamide

Tri-n-butyl(2-pyridyl)tin (0.13 ml, 0.41 mmol) anddichlorobis(triphenylphosphine)palladium(32.1 mg, 0.05 mmol) were addedto a solution ofN-[3,5-bis(trifluoromethyl)phenyl]-5-iodo-2-methoxymethoxybenzamide(0.20 g, 0.39 mmol) in N,N-dimethylformamide (8 ml), and the mixture wasstirred at 100° C. for 1.5 hours. After the reaction mixture was cooledto room temperature, it was poured into water and extracted with ethylacetate. After the ethyl acetate layer was washed successively withwater and brine, dried over anhydrous sodium sulfate, the residueobtained by evaporation of the solvent under reduced pressure waspurified by column chromatography on silica gel (n-hexane:ethylacetate=2:1→1:1) to give the title compound (37.9 mg, 20.8%) as a whitepowder.

¹H-NMR(CDCl₃): δ 3.64(3H, s), 5.53(2H, s), 7.23-7.28(1H, m), 7.36(1H, d,J=8.7 Hz), 7.65(1H, s), 7.77-7.84(2H, m), 8.20(2H, s), 8.31(1H, dd,J=8.7, 2.4 Hz), 8.68-8.70(1H, m), 8.83(1H, d, J=2.4 Hz), 10.12(1H, s).

(3)N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-(pyridin-2-yl)benzamide(Compound No. 32)

Methanol (3 ml) and concentrated hydrochloric acid (0.5 ml) were addedtoN-[3,5-bis(trifluoromethyl)phenyl]-2-methoxymethoxy-5-(pyridin-2-yl)benzamide(37.9 mg, 0.08 mmol), and the mixture was refluxed for 2 hours. Afterthe reaction mixture was cooled to room temperature, it was poured intosaturated aqueous sodium hydrogen carbonate and extracted with ethylacetate. After the ethyl acetate layer was washed successively withwater and brine, dried over anhydrous sodium sulfate, the residueobtained by evaporation of the solvent under reduced pressure waspurified by column chromatography on silica gel (n-hexane:ethylacetate=2:1) to give the title compound (16.2 mg, 47.2%) as a whitepowder.

¹H-NMR(DMSO-d₆): δ 7.13(1H, d, J=8.4 Hz), 7.33(1H, ddd, J=7.5, 6.3, 1.2Hz), 7.86-7.91(2H, m), 7.97(1H, d, J=7.8 Hz), 8.20(1H, dd, J=8.7, 2.1Hz), 8.50(2H, s), 8.59(1H, d, J=2.4 Hz), 8.64-8.66(1H, m), 10.97(1H, s),11.53(1H, s).

Example 33 Preparation of the Compound of Compound No. 33

Using 5-methoxysalicylic acid and 3,5-bis(trifluoromethyl)aniline as theraw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 56.8%.

¹H-NMR(DMSO-d₆): δ 3.77(3H, s), 6.97(1H, d, J=9.0 Hz), 7.10(1H, dd,J=9.0, 3.0 Hz), 7.43(1H, d, J=3.0 Hz), 7.84(1H, s), 8.47(2H, s),10.84(1H, s), 10.91(1H, s).

Example 34 Preparation of the Compound of Compound No. 34 (1)5-Acetyl-2-methoxybenzoic acid methyl ester

Methyl iodide (2.5 mL, 40.1 mmol) was added to a mixture of5-acetylsalicylic acid methyl ester (5.00 g, 25.7 mmol), sodiumcarbonate (7.10 g, 51.4 mmol) and N,N-dimethylformamide (25 mL) underice cooling, and the mixture was stirred at room temperature for 3hours. The reaction mixture was poured into water, neutralized byhydrochloric acid, and extracted with ethyl acetate. After the ethylacetate layer was washed successively with water and brine, dried overanhydrous sodium sulfate, the residue obtained by evaporation of thesolvent under reduced pressure was washed under suspension (isopropylether/n-hexane) to give the title compound (5.17 g, 96.5%) as a whitecrystal.

¹H-NMR(CDCl₃): δ 2.59(3H, s), 3.92(3H, s), 3.99(3H, s), 7.04(1H, d,J=8.7 Hz), 8.12(1H, dd, J=8.7, 2.4 Hz), 8.41(1H, d, J=2.4 Hz).

(2) 5-Isobutyryl-2-methoxybenzoic acid methyl ester

Methyl iodide (0.5 mL, 8.03 mmol) was added to a mixture of5-acetyl-2-methoxybenzoic acid methyl ester (0.50 g, 2.40 mmol),potassium tert-butoxide (0.81 g, 7.22 mmol) and tetrahydrofuran (10 mL),and the mixture was stirred at room temperature for 1 hour. The reactionmixture was poured into water, neutralized by hydrochloric acid, andextracted with ethyl acetate. After the ethyl acetate layer was washedsuccessively with water and brine, dried over anhydrous sodium sulfate,the residue obtained by evaporation of the solvent under reducedpressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=3:1→2:1) to give the title compound (143.1 mg,25.2%) as a light yellow oil.

¹H-NMR(CDCl₃): δ 1.22(6H, d, J=6.9 Hz), 3.52(1H, m), 3.92(3H, s),3.98(3H, s), 7.05(1H, d, J=8.7 Hz), 8.13(1H, dd, J=8.7, 2.4 Hz),8.42(1H, d, J=2.4 Hz).

(3) 5-Isobutyryl-2-methoxybenzoic acid

2N Aqueous sodium hydroxide (1 mL) was added to a solution of5-isobutyryl-2-methoxybenzoic acid methyl ester (143.1 mg, 0.60 mmol) inmethanol (5 mL), and the mixture was refluxed for 1 hour. After thereaction mixture was cooled to room temperature, it was poured into 2Nhydrochloric acid and extracted with ethyl acetate. After the ethylacetate layer was washed successively with water and brine, dried overanhydrous sodium sulfate, the solvent was evaporated under reducedpressure to give the title compound (134 mg, quantitative) as a whitecrystal.

¹H-NMR(CDCl₃): δ 1.22(6H, d, J=6.9 Hz), 3.59(1H, m), 4.15(3H, s),7.16(1H, d, J=8.7 Hz), 8.24(1H, dd, J=8.7, 2.4 Hz), 8.73(1H, d, J=2.1Hz).

(4) 5-Isobutyryl-N-[3,5-bis(trifluoromethyl)phenyl]-2-methoxybenzamide

Using 5-isobutyryl-2-methoxybenzoic acid and3,5-bis(trifluoromethyl)aniline as the raw materials, the same operationas the Example 3 gave the title compound.

Yield: 61.4%.

¹H-NMR(CDCl₃): δ 1.23(6H, d, J=6.9 Hz), 3.64(1H, m), 4.20(3H, s),7.18(1H, d, J=8.7 Hz), 7.65(1H, s), 8.19(2H, s), 8.22(1H, dd, J=8.7, 2.1Hz), 8.88(1H, d, J=2.1 Hz), 9.98(1H, s).

(5) N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-isobutyrylbenzamide(Compound No. 34).

A mixture of5-isobutyryl-N-[3,5-bis(trifluoromethyl)phenyl]-2-methoxybenzamide(143.4 mg, 0.33 mmol), 2,4,6-collidine (3 ml) and lithium iodide (53.1mg, 0.40 mmol) was refluxed for 1 hour. After the reaction mixture wascooled to room temperature, it was poured into 2N hydrochloric acid andextracted with ethyl acetate. After the ethyl acetate layer was washedwith brine, dried over anhydrous sodium sulfate, the residue obtained byevaporation of the solvent under reduced pressure was purified by columnchromatography on silica gel (n-hexane:ethyl acetate=3:1) andcrystallized by ethyl acetate/isopropyl ether to give the title compound(90.3 mg, 65.3%) as a white crystal.

¹H-NMR(DMSO-d₆): δ 1.12(6H, d, J=6.9 Hz), 3.66(1H, m), 7.12(1H, d, J=8.4Hz), 7.85(1H, s), 8.07(1H, dd, J=8.4, 2.4 Hz), 8.45(1H, d, J=2.4 Hz),8.47(2H, s), 10.93(1H, s), 11.95(1H, brs).

Example 35 Preparation of the Compound of Compound No. 35

Using 4-hydroxyisophthalic acid 1-methyl ester and3,5-bis(trifluoromethyl)aniline as the raw materials, the same operationas the Example 3 gave the title compound.

Yield: 91.5%.

¹H-NMR(DMSO-d₆): δ 3.85(3H, s), 7.12(1H, d, J=8.4 Hz), 7.86(1H, s),8.02(1H, dd, J=8.7, 2.4 Hz), 8.46-8.47(3H, m), 10.96(1H, s), 12.03(1H,brs).

-   [4-Hydroxyisophthalic acid 1-methyl ester: Refer to “Journal of the    Chemical Society”, (England), 1956, p. 3099-3107.]

Example 36 Preparation of the Compound of Compound No. 36

2N Aqueous sodium hydroxide (14 mL) was added to a suspension ofN-[3,5-bis(trifluoromethyl)phenyl]-4-hydroxyisophthalamic acid methylester (Comound No. 35; 2.85 g, 7 mmol) in a mixed solvent ofmethanol/tetrahydrofuran (14 mL+14 mL), and the mixture was refluxed for2 hours. After the reaction mixture was cooled to room temperature, 2Nhydrochloric acid (20 ml) was added and the separated solid wasfiltered, washed with water, dried to give the title compound (2.68 g,97.4%) as a white crystal.

¹H-NMR(DMSO-d₆): δ 7.10(1H, d, J=8.7 Hz), 7.82(1H, s), 7.86(1H, s),8.01(1H, dd, J=8.7, 2.4 Hz), 8.47(2H, s), 8.48(1H, d, J=2.4 Hz),10.97(1H, s), 11.98(1H, brs).

When the method described in Example 36 is referred in the followingexamples, inorganic bases such as sodium hydroxide, potassium carbonateor the like were used as the base. As the reaction solvent, solventssuch as water, methanol, ethanol, tetrahydrofuran or the like were usedalone or as a mixture.

Example 37 Preparation of the Compound of Compound No. 37

Using 4-hydroxyisophthalic acid (182 mg, 1 mmol),3,5-bis(trifluoromethyl)aniline (687 mg, 3 mmol), phosphorus trichloride(87 μL; 1 mmol) and toluene (10 mL), the same operation as the Example 3gave the title compound (151 mg, 25.0%) as a white crystal.

¹H-NMR(DMSO-d₆): δ 7.18(1H, d, J=8.7 Hz), 7.82(1H, s), 7.86(1H, s),8.11(1H, dd, J=8.7, 2.4 Hz), 8.50(2H, s), 8.54(2H, s), 8.56(1H, d, J=2.4Hz), 10.79(1H, s), 10.99(1H, s), 11.84(1H, brs).

Example 38 Preparation of the Compound of Compound No. 38 (1)4-Benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]isophthalamic acid methylester

A solution of N-[3,5-bis(trifluoromethyl)phenyl]-4-hydroxyisophthalamicacid methyl ester (Compound No. 35; 8.15 g, 20 mmol) inN,N-dimethylformamide (100 mL) was added to a suspension of sodiumhydride (60%; 1.04 g, 26 mmol) in N,N-dimethylformamide (100 mL) underice cooling, and the mixture was stirred at room temperature for 1 hour.A solution of benzyl bromide (4.45 g, 26 mmol) in N,N-dimethylformamide(10 mL) was added and the mixture was stirred at 60° C. for 3 hours.After the reaction mixture was cooled to room temperature, it was pouredinto ice and water, and extracted with ethyl acetate. After the ethylacetate layer was washed successively with water and brine, dried overanhydrous magnesium sulfate, the residue obtained by evaporation of thesolvent under reduced pressure was recrystallized from ethylacetate/n-hexane to give the title compound (5.38 g, 54.1%) as a whitesolid.

¹H-NMR(DMSO-d₆): δ 3.87(3H, s), 5.33(2H, s), 7.33-7.36(3H, m), 7.46(1H,d, J=8.7 Hz), 7.53-7.56(2H, m), 7.82(1H, s), 8.15(1H, dd, J=8.7, 2.1Hz), 8.25(1H, d, J=2.1 Hz) 8.28(2H, s), 10.87(1H, s).

(2) 4-Benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]isophthalamic acid

Using 4-benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]isophthalamic acidmethyl ester as the raw material, the same operation as the Example 36gave the title compound.

Yield: 79.7%.

¹H-NMR(DMSO-d₆): δ 5.32(2H, s), 7.32-7.34(3H, m), 7.43(1H, d, J=8.7 Hz),7.52-7.56(2H, m), 7.81(1H, s), 8.12(1H, dd, J=8.7, 2.1 Hz), 8.22(1H, d,J=2.1 Hz), 8.28(2H, s), 10.85(1H, s), 13.81(1H, brs).

(3)4-Benzyloxy-N-3-[3,5-bis(trifluoromethyl)phenyl]-N¹,N¹-dimethylisophthalamide

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (hereinafterabbreviated as WSC.HCl; 95 mg, 0.50 mmol) was added to a solution of4-benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]isophthalamic acid (242mg, 0.50 mmol), dimethylamine hydrochloride (41 mg, 0.50 mmol) andtriethylamine (51 mg, 0.50 mmol) in tetrahydrofuran (5 mL) under icecooling, and the mixture was stirred at room temperature for 3 hours.The reaction mixture was poured into water and extracted with ethylacetate. After the ethyl acetate layer was washed successively withdiluted hydrochloric acid, water and brine, dried over anhydrousmagnesium sulfate, the residue obtained by evaporation of the solventunder reduced pressure was purified by column chromatography on silicagel (hexane:ethyl acetate=1:4) to give the title compound (165 mg,64.9%) as a white solid.

¹H-NMR(DMSO-d₆): δ 2.99(6H, s) 5.29(2H, s), 7.32-7.38(4H, m),7.52-7.56(2H, m), 7.64(1H, dd, J=8.7, 2.1 Hz), 7.73(1H, d, J=2.1 Hz),7.80(1H, s), 8.28(2H, s), 10.83(1H, s).

When the method described in Example 38(3) is referred in the followingexamples, organic bases such as pyridine, triethylamine or the like wereused as the base. As the reaction solvent, solvents such asdichloromethane, tetrahydrofuran or the like were used alone or as amixture.

(4)N³-[3,5-bis(trifluoromethyl)phenyl]-4-hydroxy-N¹,N¹-dimethylisophthalamide(Compound No. 38)

A mixture of4-benzyloxy-N³-[3,5-bis(trifluoromethyl)phenyl]-N¹,N¹-dimethyl-isophthalamide(141 mg, 0.28 mmol), 5% palladium on carbon (14 mg), ethanol (5 ml) andethyl acetate (5 ml) was stirred at room temperature for 1 hour underhydrogen atmosphere. The reaction mixture was filtered and the filtratewas evaporated under reduced pressure to give the title compound (106mg, 91.2%) as a white solid.

¹H-NMR(DMSO-d₆): δ 2.98(6H, s), 7.02(1H, d, J=8.7 Hz), 7.52(1H, dd,J=8.7, 2.1 Hz), 7.84(1H, s), 7.95(1H, d, J=2.1 Hz), 8.46(2H, s),11.10(1H, brs), 11.63(1H, brs).

Example 39 Preparation of the Compound of Compound No. 39 (1)2-Benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]-5-(piperidine-1-carbonyl)benzamide

Using 4-benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]isophthalamic acid(compound of Example 38(2)) and piperidine as the raw materials, thesame operation as the Example 38(3) gave the title compound.

Yield: 56.4%.

¹H-NMR(CDCl₃): δ 1.53-1.70(6H, m), 3.44(2H, brs), 3.70(2H, brs),5.26(2H, s), 7.24(1H, d, J=8.7 Hz), 7.26(1H, s), 7.52-7.58(5H, m),7.66(2H, s), 7.74(1H, dd, J=8.7, 2.4 Hz), 8.37(1H, d, J=2.1 Hz),10.27(1H, s).

(2)N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-(piperidine-1-carbonyl)benzamide(Compound No. 39)

Using2-benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]-5-(piperidine-1-carbonyl)benzamideas the raw material, the same operation as the Example 38(4) gave thetitle compound.

Yield: 96.3%, white solid.

¹H-NMR(DMSO-d₆): δ 1.51(4H, brs), 1.60-1.65(2H, m), 3.47(4H, brs),7.04(1H, d, J=8.4 Hz), 7.48(1H, dd, J=8.4, 2.1 Hz), 7.85(1H, s),7.92(1H, d, J=2.1 Hz), 8.46(2H, s), 10.99(1H, s), 11.64(1H, brs).

Example 40 Preparation of the Compound of Compound No. 40 (1)2-Benzyloxy-5-(4-benzylpiperidine-1-carbonyl)-N-[3,5-bis(trifluoromethyl)phenyl]-benzamide

Using 4-benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]isophthalamic acid(compound of Example 38(2)) and 4-benzylpiperidine as the raw materials,the same operation as the Example 38(3) gave the title compound.

Yield: 76.7%.

¹H-NMR(CD₃OD): δ 1.18-1.38(2H, m), 1.67(1H, brs), 1.74(1H, brs),1.84-1.93(1H, m), 2.60(2H, d, J=7.2 Hz), 2.83(1H, brs), 3.10(1H, brs),3.78(1H, brs), 4.59(1H, brs), 5.34(2H, s), 7.15-7.18(3H, m),7.24-7.28(2H, m), 7.40-7.46(4H, m), 7.57-7.63(3H, m), 7.65(1H, dd,J=8.7, 2.4 Hz), 7.96(2H, s), 8.05(1H, d, J=2.1 Hz).

(2)N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-(4-benzylpiperidine-1-carbonyl)benzamide(Compound No. 40)

Using2-benzyloxy-5-(4-benzylpiperidine-1-carbonyl)-N-[3,5-bis(trifluoromethyl)phenyl]-benzamideas the raw material, the same operation as the Example 38(4) gave thetitle compound.

Yield: 54.3%, white solid.

¹H-NMR(DMSO-d₆): δ 1.08-1.22(2H, m), 1.59-1.62(2H, m), 1.77-1.80(1H, m),2.50-2.55(2H, m), 2.87(2H, brs), 3.75(1H, br), 4.39(1H, br), 7.06(1H, d,J=8.4 Hz), 7.17-7.20(3H, m), 7.28(2H, t, J=7.2 Hz), 7.49(1H, dd, J=8.4,2.1 Hz), 7.84(1H, s), 7.93(1H, d, J=2.1 Hz), 8.47(2H, s), 10.89(1H, s),11.65(1H, s).

Example 41 Preparation of the Compound of Compound No. 41 (1)2-Methoxy-5-sulfamoylbenzoic acid

2N Aqueous sodium hydroxide (30 mL, 60 mmol) was added to a solution ofmethyl 2-methoxy-5-sulfamoylbenzoate (4.91 g, 20 mmol) in methanol (30mL), and the mixture was stirred at room temperature for 1 hour. Thereaction mixture was poured into 2N hydrochloric acid, and the separatedsolid was filtered to give the title compound (4.55 g, 98.3%) as a whitesolid.

¹H-NMR(DMSO-d₆): δ 3.89(3H, s), 7.30(1H, d, J=8.7 Hz), 7.32(2H, s),7.92(1H, dd, J=8.7, 2.7 Hz), 8.09(1H, d, J=2.7 Hz), 13.03(1H, br).

(2) N-[3,5-Bis(trifluoromethyl)phenyl]-2-methoxy-5-sufamoylbenzamide

Using 2-methoxy-5-sulfamoylbenzoic acid and3,5-bis(trifluoromethyl)aniline as the raw materials, the same operationas the Example 12(3) gave the title compound.

Yield: 24.2%.

¹H-NMR(DMSO-d₆): δ 3.97(3H, s), 7.38(2H, s), 7.39(1H, d, J=8.7 Hz),7.85(1H, s), 7.96(1H, dd, J=8.7, 2.4 Hz), 8.06(1H, d, J=2.4 Hz),8.43(2H, s), 10.87(1H, s).

(3)N-[3,5-Bis(trifluoromethyl)phenyl]-5-dimethylsufamoyl-2-methoxybenzamide

A suspension ofN-[3,5-bis(trifluoromethyl)phenyl]-2-methoxy-5-sufamoylbenzamide (442mg, 1.0 mmol), methyl iodide (710 mg, 5.0 mmol), sodium carbonate (415mg, 3.0 mmol) and acetonitrile (10 mL) was refluxed for 3 hours. Afterthe reaction mixture was cooled to room temperature, it was poured intowater and extracted with ethyl acetate. After the ethyl acetate layerwas washed successively with water and brine, dried over anhydrousmagnesium sulfate, the residue obtained by evaporation of the solventunder reduced pressure was recrystallized from n-hexane/ethyl acetate togive the title compound (207 mg, 44.1%) as a white solid.

¹H-NMR(DMSO-d₆): δ 2.62(6H, s), 3.99(3H, s), 7.45(1H, d, J=9.0 Hz),7.85(1H, s), 7.91(1H, dd, J=8.7, 2.4 Hz), 7.95(1H, d, J=2.4 Hz) 8.43(2H,s), 10.90(1H, s).

(4)N-[3,5-Bis(trifluoromethyl)phenyl]-5-dimethylsufamoyl-2-hydroxybenzamide(Compound No. 41)

UsingN-[3,5-bis(trifluoromethyl)phenyl]-5-dimethylsufamoyl-2-methoxybenzamideas the raw material, the same operation as the Example 34(5) gave thetitle compound.

Yield: 45.5%.

¹H-NMR(DMSO-d₆): δ 2.61(6H, s), 7.20(1H, d, J=8.7 Hz), 7.77(1H, dd,J=8.7, 2.1 Hz), 7.86(1H, s), 8.14(1H, d, J=2.1 Hz) 8.45(2H, s),11.16(1H, s), 12.15(1H, br).

Example 42 Preparation of the Compound of Compound No. 42 (1)N-[3,5-Bis(trifluoromethyl)phenyl]-2-methoxy-5-(pyrrole-1-sulfonyl)benzamide

A mixture ofN-[3,5-bis(trifluoromethyl)phenyl]-2-methoxy-5-sulfamoylbenzamide(compound of Example 41(2); 442 mg, 1 mmol),2,5-dimethoxytetrahydrofuran (159 mg, 1.2 mmol) and acetic acid (5 mL)was refluxed for 2 hours. After the reaction mixture was cooled to roomtemperature, it was poured into water and extracted with ethyl acetate.After the ethyl acetate layer was washed successively with water,saturated aqueous sodium hydrogen carbonate and brine, dried overanhydrous magnesium sulfate, the residue obtained by evaporation of thesolvent under reduced pressure was purified by column chromatography onsilica gel (n-hexane:ethyl acetate=3:2) to give the title compound(436.5 mg, 88.6%) as a white solid.

¹H-NMR(DMSO-d₆): δ 3.96(3H, s), 6.36(2H, dd, J=2.4, 2.1 Hz), 7.37(2H,dd, J=2.4, 2.1 Hz), 7.42(1H, d, J=9.0 Hz), 7.85(1H, s), 8.80(1H, dd,J=9.0, 2.4 Hz) 8.18(1H, d, J=2.7 Hz), 8.38(2H, s), 10.92(1H, s).

(2)N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-(pyrrole-1-sulfonyl)benzamide(Compound No. 42)

UsingN-[3,5-bis(trifluoromethyl)phenyl]-2-methoxy-5-(pyrrole-1-sulfonyl)benzamideas the raw material, the same operation as the Example 34(5) gave thetitle compound.

Yield: 79.4%.

¹H-NMR(DMSO-d₆) δ 6.36(2H, dd, J=2.4, 2.1 Hz), 7.18(1H, d, J=9.0 Hz),7.34(2H, dd, J=2.4, 2.1 Hz), 7.86(1H, s), 7.99(1H, dd, J=9.0, 2.7 Hz)8.31(1H, d, J=2.7 Hz), 8.42(2H, s), 10.98(1H, s).

Example 43 Preparation of the Compound of Compound No. 43

Using N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-nitrobenzamide(Compound No. 8) as the raw material, the same operation as the Example38(4) gave the title compound.

Yield: 98.0%.

¹H-NMR(DMSO-d₆): δ 4.79(2H, brs), 6.76(1H, d, J=2.1 Hz), 6.76(1H, s),7.09(1H, dd, J=2.1, 1.2 Hz), 7.80(1H, s), 8.45(2H, s), 10.30(1H, br),10.84(1H, s).

Example 44 Preparation of the Compound of Compound No. 44

Using 5-dimethylaminosalicylic acid and 3,5-bis(trifluoromethyl)anilineas the raw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 28.8%.

¹H-NMR(DMSO-d₆): δ 2.85(6H, s), 6.92(1H, d, J=9.0 Hz), 7.01(1H, dd,J=8.7, 3.0 Hz), 7.22(1H, d, J=3.0 Hz), 7.84(1H, s), 8.47(2H, s),10.62(1H, s), 10.83(1H, s).

Example 45 Preparation of the Compound of Compound No. 45

Benzoyl chloride (155 mg, 1.1 mmol) was added to a mixture of5-amino-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide (CompoundNo. 43; 364 mg, 1 mmol), pyridine (95 mg, 1.2 mmol) and tetrahydrofuran(10 mL) under ice cooling, and the mixture was stirred for 1 hour. Thereaction mixture was poured into water and extracted with ethyl acetate.After the ethyl acetate layer was washed successively with water andbrine, dried over anhydrous magnesium sulfate, the residue obtained byevaporation of the solvent under reduced pressure was purified by columnchromatography on silica gel (n-hexane:ethyl acetate=4:1) to give thetitle compound (121 mg, 25.7%) as a white solid.

¹H-NMR(DMSO-d₆): δ 7.04(1H, d, J=8.7 Hz), 7.51-7.62(3H, m), 7.81(1H, dd,J=8.7, 2.4 Hz), 7.83(1H, s), 7.98(2H, d, J=7.2 Hz), 8.22(1H, d, J=2.4Hz), 8.49(2H, s), 10.27(1H, s), 10.89(1H, s), 11.07(1H, s).

Example 46 Preparation of the Compound of Compound No. 46

4-Dimethylaminopyridine (3 mg) and phenylisocyanate (30 μL, 0.28 mmol)were added to a solution of5-amino-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide (CompoundNo. 43; 100.2 mg, 0.28 mmol) in acetonitrile (4 ml), and the mixture wasstirred at 60° C. for 5 minutes. After the reaction mixture was cooledto room temperature, the residue obtained by evaporation of the solventunder reduced pressure was purified by column chromatography on silicagel (n-hexane:ethyl acetate=1:1) to give the title compound (54.8 mg,41.2%) as a light brown solid.

¹H-NMR(DMSO-d₆): δ 6.93-6.98(1H, m), 6.97(1H, d, J=9.3 Hz), 7.27(2H, t,J=7.8 Hz), 7.34-7.46(2H, m), 7.50(1H, dd, J=9.0, 2.4 Hz), 7.83(1H, s),7.88(1H, s), 8.47(2H, s), 8.56(1H, s), 8.63(1H, s), 10.87(1H, s),10.89(1H, s).

Example 47 Preparation of the Compound of Compound No. 47

Using 5-amino-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide(Compound No. 43) and phenylisothiocyanate as the raw materials, thesame operation as the Example 46 gave the title compound.

Yield: 66.3%.

¹H-NMR(DMSO-d₆): δ 7.00(1H, d, J=8.4 Hz), 7.13(1H, tt, J=7.5, 1.2 Hz),7.34(2H, t, J=7.8 Hz), 7.45-7.51(3H, m), 7.84(1H, s), 7.87(1H, d, J=2.7Hz), 8.47(2H, s), 9.65(1H, s), 9.74(1H, s), 10.84(1H, s), 11.32(1H, s).

Example 48 Preparation of the Compound of Compound No. 48

Using 5-[(4-nitrophenyl)diazenyl]salicylic acid and3,5-bis(trifluoromethyl)aniline as the raw materials, the same operationas the Example 3 gave the title compound.

Yield: 11.3%.

¹H-NMR(DMSO-d₆): δ 7.23(1H, d, J=9.0 Hz), 7.87(1H, s), 8.06(2H, d, J=9.0Hz), 8.10(1H, dd, J=9.0, 2.4 Hz), 8.44(2H, d, J=9.0 Hz), 8.50(2H, s),8.53(1H, d, J=2.4 Hz), 11.13(1H, s), 12.14(1H, br).

Example 49 Preparation of the Compound of Compound No. 49

Using 5-({[(4-pyridin-2-yl)sulfamoyl]phenyl}diazenyl)salicylic acid and3,5-bis(trifluoromethyl)aniline as the raw materials, the same operationas the Example 3 gave the title compound.

Yield: 7.9%.

¹H-NMR(DMSO-d₆): δ 6.87(1H, t, J=6.0 Hz), 7.22(1H, d, J=8.7 Hz),7.21-7.23(1H, m), 7.77(1H, t, J=8.4 Hz), 7.87(1H, s), 7.95-7.98(3H, m),8.03-8.07(4H, m), 8.47(1H, d, J=2.4 Hz), 8.49(2H, s), 11.14(1H, s),12.03(1H, br).

Example 50 Preparation of the Compound of Compound No. 50 (1)4-Acetylamino-5-chloro-2-methoxybenzoic acid

Using 4-acetylamino-5-chloro-2-methoxybenzoic acid methyl ester as theraw material, the same operation as the Example 36 gave the titlecompound.

Yield: 88.0%.

¹H-NMR(DMSO-d₆): δ 2.16(3H, s), 3.78(3H, s), 7.72(1H, s), 7.77(1H, s),9.57(1H, s), 12.74(1H, s).

(2)4-Acetylamino-N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-methoxybenzamide

Using 4-acetylamino-5-chloro-2-methoxybenzoic acid and3,5-bis(trifluoromethyl)aniline as the raw materials, the same operationas the Example 12(3) gave the title compound.

Yield: 23.8%.

¹H-NMR(DMSO-d₆): δ 2.17(3H, s), 3.89(3H, s), 7.77-7.82(3H, m),8.45-8.49(2H, m), 9.66(1H, s), 10.68(1H, s).

(3)4-Acetylamino-N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydoxybenzamide(Compound No. 50)

Using4-acetylamino-N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-methoxybenzamideas the raw material, the same operation as the Example 34(5) gave thetitle compound.

Yield: 72.8%.

¹H-NMR(DMSO-d₆): δ 2.17(3H, s), 7.75(1H, s), 7.82(1H, s), 7.95(1H, s),8.44(2H, s), 9.45(1H, s), 11.16(1H, brs), 11.63(1H, brs).

Example 51 Preparation of the Compound of Compound No. 51

Using 4-chlorosalicylic acid and 3,5-bis(trifluoromethyl)aniline as theraw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 55.8%.

¹H-NMR(DMSO-d₆): δ 7.05-7.08(2H, m), 7.84-7.87(2H, m), 8.45(2H, s),10.84(1H, s) 11.64(1H, brs).

Example 52 Preparation of the Compound of Compound No. 52

Using 6-hydroxysalicylic acid and 3,5-bis(trifluoromethyl)aniline as theraw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 86.9%.

¹H-NMR(DMSO-d₆): δ 6.36(2H,d,J=8.4 Hz), 7.13(1H,t,J=8.4 Hz), 7.79(1H,s), 8.38(2H, s), 11.40(2H,brs), 11.96(1H, brs).

Example 53 Preparation of the Compound of Compound No. 53

Using 4-methylsalicylic acid and 3,5-bis(trifluoromethyl)aniline as theraw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 42.9%.

¹H-NMR(DMSO-d₆): δ 2.32(3H, s) 6.82(1H, d, J=6.6 Hz) 6.84(1H, s)7.83(1H, s) 7.84(1H, d, J=8.5 Hz) 8.47(2H, s) 10.76(1H, s) 11.44(1H, s).

Example 54 Preparation of the Compound of Compound No. 54

Using 5-bromo-4-hydroxysalicylic acid and3,5-bis(trifluoromethyl)aniline as the raw materials, the same operationas the Example 3 gave the title compound.

Yield: 82.4%.

¹H-NMR(CDCl₃): δ 5.89(1H, s) 6.70(1H, s) 7.69(2H, s) 7.95(1H, s)8.12(2H, s) 11.62(1H, s).

Example 55 Preparation of the Compound of Compound No. 55

Using 4-hydroxysalicylic acid and 3,5-bis(trifluoromethyl)aniline as theraw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 29.9%.

¹H-NMR(DMSO-d₆): δ 6.37(1H, d, J=2.5 Hz), 6.42(1H, dd, J=8.8, 2.5 Hz),7.81(1H, s), 7.86(1H, d, J=8.5 Hz), 8.44(2H, s), 10.31(1H, s), 10.60(1H,s), 11.77(1H, s).

Example 56 Preparation of the Compound of Compound No. 56

Using 3,5-dichlorosalicylic acid and 3,5-bis(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 44.8%.

¹H-NMR(DMSO-d₆): δ 7.85(1H, d, J=2.5 Hz), 7.91(1H, s), 8.01(1H, d, J=2.5Hz), 8.42(2H, s), 11.10(1H, s).

Example 57 Preparation of the Compound of Compound No. 57

Using 3-hydroxysalicylic acid and 3,5-bis(trifluoromethyl)aniline as theraw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 22.7%.

¹H-NMR(DMSO-d₆): δ 6.81(1H, t, J=8.0 Hz), 7.01(1H, dd, J=8.0, 1.5 Hz),7.35(1H, dd, J=8.0, 1.5 Hz), 7.84(1H, s), 8.46(2H, s), 9.56(1H, s),10.79(1H, s), 10.90(1H, brs).

Example 58 Preparation of the Compound of Compound No. 58

Using 3-methylsalicylic acid and 3,5-bis(trifluoromethyl)aniline as theraw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 54.9%.

¹H-NMR(DMSO-d₆): δ 2.22(3H, s), 6.94(1H, t, J=7.4 Hz), 7.42(1H, d, J=7.4Hz), 7.84-7.85(2H, m), 8.47(2H, s), 10.87(1H, s), 11.87(1H, s).

Example 59 Preparation of the Compound of Compound No. 59

Using 3-methoxysalicylic acid and 3,5-bis(trifluoromethyl)aniline as theraw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 34.6%.

¹H-NMR(DMSO-d₆): δ 3.85(3H, s), 6.94(1H, t, J=8.0 Hz), 7.20(1H, dd,J=8.0, 1.4 Hz), 7.44(1H, dd, J=8.0, 1.4 Hz), 7.84(1H, s), 8.45(2H, s),10.82(1H, s), 10.94(1H, brs).

Example 60 Preparation of the Compound of Compound No. 60

Using 5-[(1,1,3,3-tetramethyl)butyl]salicylic acid and3,5-bis(trifluoromethyl)aniline as the raw materials, the same operationas the Example 3 gave the title compound.

Yield: 64.2%.

¹H-NMR(DMSO-d₆): δ 0.70(9H, s), 1.35(6H, s), 1.72(2H, s), 6.95(1H, d,J=8.4 Hz), 7.50(1H, dd, J=8.0, 2.1 Hz), 7.83(1H, s), 7.84(1H, d, J=2.1Hz), 8.46(1H, s), 10.77(1H, s), 11.20(1H, s).

Example 61 Preparation of the Compound of Compound No. 61

Using 3,5,6-trichlorosalicylic acid and 3,5-bis(trifluoromethyl)anilineas the raw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 26.2%.

¹H-NMR(DMSO-d₆): δ 7.88(1H, s), 7.93(1H, s), 8.33(2H, s), 10.88(1H, s),11.36(1H, s).

Example 62 Preparation of the Compound of Compound No. 62

Using 3,5-bis[(1,1-dimethyl)ethyl]salicylic acid and3,5-bis(trifluoromethyl)aniline as the raw materials, the same operationas the Example 3 gave the title compound.

Yield: 65.0%.

¹H-NMR(DMSO-d₆): δ 1.34(9H, s), 1.40(9H, s), 7.49(1H, d, J=2.2 Hz),7.82(1H, d, J=2.2 Hz), 7.91(1H, s), 8.40(2H, s), 10.82(1H, s), 12.44(1H,s).

Example 63 Preparation of the Compound of Compound No. 63

Using 6-fluorosalicylic acid and 3,5-bis(trifluoromethyl)aniline as theraw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 35.9%.

¹H-NMR(DMSO-d₆): δ 6.73-6.82(2H, m), 7.32(1H, ddd, J=1.4, 8.5, 15.3 Hz),7.83(1H, s), 8.39(2H, s), 10.50(1H, d, J=1.4 Hz), 11.11(1H, s).

Example 64 Preparation of the Compound of Compound No. 64

Using 3-chlorosalicylic acid and 3,5-bis(trifluoromethyl)aniline as theraw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 61.3%.

¹H-NMR(DMSO-d₆): δ 7.05(1H, dd, J=7.6, 8.0 Hz), 7.69(1H, dd, J=1.4, 13.3Hz), 7.90(1H, s), 7.93(1H, dd, J=1.4, 8.0 Hz), 8.44(2H, s), 11.01(1H,s), 11.92(1H, br.s).

Example 65 Preparation of the Compound of Compound No. 65

Using 4-methoxysalicylic acid and 3,5-bis(trifluoromethyl)aniline as theraw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 14.2%.

¹H-NMR(DMSO-d₆): δ 3.81(3H, s), 6.54(1H, d, J=2.5 Hz), 6.61(1H, dd,J=2.5, 8.8 Hz), 7.83(1H, s), 7.95(1H, d, J=8.8 Hz), 8.45(2H, s),10.69(1H, s), 11.89(1H, s).

Example 66 Preparation of the Compound of Compound No. 66

Using 6-methoxysalicylic acid and 3,5-bis(trifluoromethyl)aniline as theraw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 63.1%.

¹H-NMR(DMSO-d₆): δ 3.24(3H, s), 6.03(1H, d, J=8.0 Hz), 6.05(1H, d, J=8.5Hz), 6.71(1H, dd, J=8.2, 8.5 Hz), 7.25(1H, s), 7.88(2H, s), 9.67(1H, s),10.31(1H, s)

Example 67 Preparation of the Compound of Compound No. 67

Using 5-amino-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide(Compound No. 43) and methanesulfonyl chloride as the raw materials, thesame operation as the Example 45 gave the title compound.

Yield: 22.6%.

¹H-NMR(DMSO-d₆): δ 2.93(3H, s), 7.02(1H, d, J=8.4 Hz), 7.31(1H, dd,J=8.4, 2.7 Hz), 7.68(1H, d, J=2.7 Hz), 7.83(1H, s), 8.46(2H, s),9.48(1H, s), 10.85(1H, s), 11.15(1H, s).

Example 68 Preparation of the Compound of Compound No. 68

Using 5-amino-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide(Compound No. 43) and benzenesulfonyl chloride as the raw materials, thesame operation as the Example 45 gave the title compound.

Yield: 45.3%.

¹H-NMR(DMSO-d₆): δ 6.89(1H, d, J=8.7 Hz), 7.10(1H, dd, J=8.7, 2.7 Hz),7.51-7.64(4H, m), 7.68-7.71(2H, m), 7.81(1H, s), 8.42(2H, s), 10.03(1H,s), 10.87(1H, s), 11.13(1H, brs).

Example 69 Preparation of the Compound of Compound No. 69

Using 5-amino-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide(Compound No. 43) and acetyl chloride as the raw materials, the sameoperation as the Example 45 gave the title compound.

Yield: 44.8%.

¹H-NMR(DMSO-d₆): δ 2.02(3H, s), 6.97(1H, d, J=8.7 Hz), 7.61(1H, dd,J=8.7, 2.7 Hz), 7.82(1H, s), 7.99(1H, d, J=2.7 Hz), 8.46(2H, s),9.90(1H, s), 10.85(1H, s), 10.94(1H, s).

Example 70 Preparation of the Compound of Compound No. 70

Using N-[3,5-bis(trifluoromethyl)phenyl]-2-methoxy-5-sulfamoylbenzamide(compound of Example 41(2)) as the raw material, the same operation asthe Example 34(5) gave the title compound.

Yield: 59.9%.

¹H-NMR(DMSO-d₆): δ 7.17(1H, d, J=8.7 Hz), 7.31(2H, s), 7.85(1H, s),7.86(1H, dd, J=8.4, 2.4 Hz), 8.26(1H, d, J=2.7 Hz), 8.47(2H, s),10.95(1H, s), 11.90(1H, s).

Example 71 Preparation of the Compound of Compound No. 71

Using 1-hydroxynaphthalene-2-carboxylic acid and3,5-bis(trifluoromethyl)aniline as the raw materials, the same operationas the Example 3 gave the title compound.

Yield: 65.5%.

¹H-NMR(DMSO-d₆): δ 7.51(1H, d, J=9.0 Hz), 7.60(1H, td, J=7.8, 0.9 Hz),7.70(1H, td, J=7.8, 0.9 Hz), 7.89(1H, s), 7.93(1H, d, J=8.4 Hz),8.09(1H, d, J=9.0 Hz), 8.33(1H, d, J=8.7 Hz), 8.51(2H, s), 10.92(1H, s),13.36(1H, s).

Example 72 Preparation of the Compound of Compound No. 72

Using 3-hydroxynaphthalene-2-carboxylic acid and3,5-bis(trifluoromethyl)aniline as the raw materials, the same operationas the Example 3 gave the title compound.

Yield: 46.9%.

¹H-NMR(DMSO-d₆): δ 7.36-7.41(2H, m), 7.50-7.55(1H, m), 7.79(1H, d, J=8.2Hz), 7.85(1H, d, J=0.6 Hz), 7.96(1H, d, J=8.0 Hz), 8.51(2H, s),10.98(1H, s), 11.05(1H, s).

Example 73 Preparation of the Compound of Compound No. 73

Using 2-hydroxynaphthalene-1-carboxylic acid and3,5-bis(trifluoromethyl)aniline as the raw materials, the same operationas the Example 3 gave the title compound.

Yield: 30.2%.

¹H-NMR(DMSO-d₆): δ 7.27(1H, d, J=8.8 Hz), 7.32-7.38(1H, m),7.45-7.50(1H, m), 7.72(1H, d, J=8.5 Hz), 7.82-7.93(3H, m), 8.50(1H, s),10.28(1H, s), 11.07(1H, brs).

Example 74 Preparation of the Compound of Compound No. 74 (1)4-Bromo-3-hydroxythiophene-2-carboxylic acid

A solution of 4-bromothiophene-2-carboxylic acid methyl ester (500 mg,2.1 mmol), sodium hydroxide (261 mg, 6.3 mmol) in a mixed solvent ofmethanol/water (2.5 mL+2.5 mL) was refluxed for 2 hours. After thereaction mixture was cooled to room temperature, 2N hydrochloric acidwas added to adjust pH to 1, and it was diluted with ethyl acetate. Theethyl acetate layer was washed successively with water and brine, anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure to give the title compound (326 mg, 69.4%) as a redbrown powder.

¹H-NMR(CDCl₃): δ 4.05(1H, brs), 7.40(1H, s).

(2)4-Bromo-3-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]thiophene-2-carboxamide(Compound No. 74)

Using 4-bromo-3-hydroxythiophene-2-carboxylic acid and3,5-bis(trifluoromethyl)aniline as the raw materials, the same operationas the Example 3 gave the title compound.

Yield: 82.4%.

¹H-NMR(CDCl₃): δ 7.42(1H, s), 7.67(1H, brs), 7.78(1H, brs), 8.11(2H, s),9.91(1H, brs).

Example 75 Preparation of the Compound of Compound No. 75

Phosphorus oxychloride (0.112 ml, 1.2 mmol) was added to a solution of5-chloro-2-hydroxynicotinic acid (174 mg, 1 mmol),3,5-bis(trifluoromethyl)aniline (275 mg, 1.2 mmol), pyridine (316 mg, 4mmol) in tetrahydrofuran/dichloromethane (20 mL+10 mL), and the mixturewas stirred at room temperature for 2 hours. The reaction mixture waspoured into ethyl acetate (100 mL) and 0.2N hydrochloric acid (100 mL),filtered through celite after stirring for 30 minutes, and the waterlayer was extracted with ethyl acetate. After the combined ethyl acetatelayer was washed successively with water and brine, dried over anhydrousmagnesium sulfate, the residue obtained by evaporation of the solventunder reduced pressure was purified by column chromatography on silicagel (n-hexane:ethyl acetate=2:1→1:1), washed with ethanol undersuspension to give the title compound (183 mg, 47.6%) as a whitecrystal.

mp>270° C.

¹H-NMR(DMSO-d₆): δ 7.83(1H, s), 8.15(1H, d, J=3.3 Hz), 8.36(1H, d, J=3.0Hz), 8.40(2H, s), 12.43(1H, s).

When the preparation method described in Example 75 is referred in thefollowing examples, phosphorus oxychloride was used as the condensatingagent (acid halogenating agent). Pyridine was used as the base. As thereaction solvent, solvents such as dichloromethane, tetrahydrofuran orthe like were used alone or as a mixture.

Example 76 Preparation of the Compound of Compound No. 76

Using 3-hydroxypyridine-2-carboxylic acid and3,5-bis(trifluoromethyl)aniline as the raw materials, the same operationas the Example 75 gave the title compound.

Yield: 45.0%.

¹H-NMR(CDCl₃): δ 7.40(1H, dd, J=8.4, 1.8 Hz), 7.46(1H, dd, J=8.4, 4.2Hz), 7.68(1H, s), 8.16(1H, dd, J=4.2, 1.2 Hz), 8.25(2H, s), 10.24(1H,s), 11.42(1H, s).

Example 77 Preparation of the Compound of Compound No. 77

A solution of 6-chloro-oxindole (184 mg, 1.1 mmol) in tetrahydrofuran (5ml) and triethylamine (0.3 mL) were added to a solution of3,5-bis(trifluoromethyl)phenylisocyanate (255 mg, 1.0 mmol) intetrahydrofuran (5 mL) under argon atmosphere, and the mixture wasstirred at room temperature for 4 hours. The reaction mixture was pouredinto diluted hydrochloric acid and extracted with ethyl acetate. Theethyl acetate layer was washed successively with water and brine, anddried over anhydrous magnesium sulfate. The residue obtained byevaporation of the solvent under reduced pressure was purified by columnchromatography on silica gel (n-hexane:ethyl acetate=4:1) to give thetitle compound (172.2 mg, 40.7%) as a pink solid.

¹H-NMR(DMSO-d₆): δ 3.97(2H, s), 7.29(1H, dd, J=8.1, 2.1 Hz), 7.41(1H, d,J=8.1 Hz), 7.88(1H, s), 8.04(1H, d, J=2.1 Hz), 8.38(2H, s), 10.93(1H,s).

Example 78 Preparation of the Compound of Compound No. 78

Using 3,5-bis(trifluoromethyl)phenylisocyanate and oxindole as the rawmaterials, the same operation as the Example 77 gave the title compound.

Yield: 44.8%.

¹H-NMR(DMSO-d₆): δ 3.98(2H, s), 7.22(1H, td, J=7.8, 1.2 Hz),7.33-7.40(2H, m), 7.87(1H, s), 8.02(1H, d, J=7.8 Hz), 8.38(2H, s),11.00(1H, s).

Example 79 Preparation of the Compound of Compound No. 79

Using 3,5-bis(trifluoromethyl)phenylisocyanate and 5-chlorooxindole asthe raw materials, the same operation as the Example 77 gave the titlecompound.

Yield: 31.1%.

¹H-NMR(DMSO-d₆): δ 3.99(2H, s), 7.41(1H, dd, J=8.7, 2.4 Hz), 7.47(1H, d,J=2.1 Hz), 7.87(1H, s), 8.01(1H, d, J=8.4 Hz), 8.38(2H, s), 10.93(1H,s).

Example 80 Preparation of the Compound of Compound No. 80

Using 3-hydroxyquinoxaline-2-carboxylic acid and3,5-bis(trifluoromethyl)aniline as the raw materials, the same operationas the Example 3 gave the title compound.

Yield: 2.7%.

¹H-NMR(DMSO-d₆): δ 7.40-7.45(2H, m), 7.69(1H, td, J=8.4, 1.5 Hz),7.90-7.93(2H, m), 8.41(2H, s), 11.64(1H, s), 13.02(1H, s).

Example 81 Preparation of the Compound of Compound No. 81

Using 5-chlorosalicylic acid and 2,5-bis(trifluoromethyl)aniline as theraw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 3.6%.

¹H-NMR(CDCl₃): δ 7.03(1H, d, J=8.7 Hz), 7.43-7.48(2H, m), 6.61(1H, d,J=8.1 Hz), 7.85(1H, d, J=8.4 Hz), 8.36(1H, brs), 8.60(1H, s), 11.31(1H,s).

Example 82 Preparation of the Compound of Compound No. 82

Using N-[2,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide(Compound No. 81) and acetyl chloride as the raw materials, the sameoperation as the Example 5 gave the title compound.

Yield: 6.6%.

¹H-NMR(CDCl₃): δ 2.35(3H, s), 7.17(1H, d, J=8.7 Hz), 7.54(1H, dd, J=8.7,2.4 Hz), 7.55(1H, d, J=8.1 Hz), 7.80(1H, d, J=8.1 Hz), 7.95(1H, d, J=2.4Hz), 8.60(1H, s), 8.73(1H, s).

Example 83 Preparation of the Compound of Compound No. 83

Using 5-bromosalicylic acid and 2,5-bis(trifluoromethyl)aniline as theraw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 24.0%.

¹H-NMR(DMSO-d₆): δ 7.03(1H, d, J=8.7 Hz), 7.65(1H, dd, J=8.7, 2.7 Hz),7.76(1H, d, J=8.4 Hz), 8.03(1H, d, J=8.1 Hz) 8.11(1H, d, J=2.7 Hz),8.74(1H, s), 11.02(1H, s), 12.34(1H, s).

Example 84 Preparation of the Compound of Compound No. 84

Using 5-methylsalicylic acid and 2,5-bis(trifluoromethyl)aniline as theraw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 1.5%.

¹H-NMR(CDCl₃): δ 2.36(3H, s), 6.97(1H, d, J=8.4 Hz), 7.23(1H, s),7.32(1H, dd, J=8.4, 1.5 Hz), 7.57(1H, d, J=8.4 Hz), 7.83(1H, d, J=8.4Hz), 8.46(1H, s), 8.69(1H, s), 11.19(1H, s).

Example 85 Preparation of the Compound of Compound No. 85

Using 5-chlorosalicylic acid and 3-fluoro-5-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 62.0%.

¹H-NMR(DMSO-d₆): δ 7.04(1H, d, J=8.7 Hz), 7.42(1H, d, J=8.4 Hz),7.48(1H, dd, J=9.0, 3.0 Hz), 7.85(1H, d, J=2.4 Hz), 7.94(1H, dd, J=11.4,2.1 Hz), 7.99(1H, s), 10.73(1H, s), 11.46(1H, s).

Example 86 Preparation of the Compound of Compound No. 86

Using 5-bromosalicylic acid and 3-bromo-5-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 73.3%.

¹H-NMR(DMSO-d₆): δ 6.99(1H, d, J=9.0 Hz), 7.60(1H, dd, J=9.0, 2.4 Hz),7.72(1H, s), 7.97(1H, d, J=2.7 Hz), 8.16(1H, s), 8.28(1H, s), 10.69(1H,s), 11.45(1H, s).

Example 87 Preparation of the Compound of Compound No. 87

Using 5-chlorosalicylic acid and 2-fluoro-5-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 77.9%.

¹H-NMR(DMSO-d₆): δ 7.07(1H, d, J=9.0 Hz), 7.52(1H, dd, J=9.0, 2.7 Hz),7.58-7.61(2H, m), 7.95(1H, d, J=2.7 Hz), 8.71(1H, d, J=7.5 Hz),10.90(1H, s), 12.23(1H, s).

Example 88 Preparation of the Compound of Compound No. 88

Using 5-chlorosalicylic acid and 2-chloro-5-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 49.1%.

¹H-NMR(DMSO-d₆): δ 7.09(1H, d, J=9.0 Hz), 7.53(1H, dd, J=9.0, 3.0 Hz),7.55(1H, dd, J=8.4, 2.7 Hz), 7.83(1H, d, J=8.4 Hz), 7.98(1H, d, J=3.0Hz), 8.88(1H, d, J=2.7 Hz), 11.14(1H, s), 12.39(1H, s).

Example 89 Preparation of the Compound of Compound No. 89

Using 5-chloro-N-[2-chloro-5-(trifluoromethyl)phenyl]-2-hydroxybenzamide(Compound No. 88) and acetyl chloride as the raw materials, the sameoperation as the Example 5 gave the title compound.

Yield: 34.0%.

¹H-NMR(CDCl₃): δ 2.39(3H, s), 7.16(1H, d, J=8.7 Hz), 7.37(1H, ddd,J=8.7, 2.4, 0.6 Hz), 7.51-7.56(2H, m), 7.97(1H, d, J=3.0 Hz), 8.85(1H,s), 8.94(1H, d, J=1.8 Hz).

Example 90 Preparation of the Compound of Compound No. 90

Using 5-bromosalicylic acid and 2-chloro-5-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 34.2%.

¹H-NMR(DMSO-d₆): δ 7.04(1H, d, J=8.7 Hz), 7.56(1H, ddd, J=8.1, 2.4, 1.2Hz), 7.64(1H, dd, J=8.7, 2.7 Hz), 7.83(1H, dd, J=8.1, 1.2 Hz), 8.11(1H,d, J=2.7 Hz), 8.87(1H, d, J=2.4 Hz), 11.12(1H, s), 12.42(1H, s).

Example 91 Preparation of the Compound of Compound No. 91

Using 5-chlorosalicylic acid and 2-nitro-5-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 8.1%.

¹H-NMR(DMSO-d₆): δ 7.08(1H, d, J=9.0 Hz), 7.53(1H, dd, J=8.7, 2.7 Hz),7.73(1H, dd, J=8.4, 1.8 Hz), 7.95(1H, d, J=3.0 Hz), 8.36(1H, d, J=8.7Hz), 9.01(1H, d, J=1.8 Hz), 12.04(1H, s), 12.20(1H, s).

Example 93 Preparation of the Compound of Compound No. 93

Using 5-chlorosalicylic acid and 2-methyl-5-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 73.3%.

¹H-NMR(DMSO-d₆): δ 2.39(3H, s), 7.07(1H, d, J=8.7 Hz), 7.44-7.54(3H, m),7.99(1H, d, J=3.0 Hz), 8.43(1H, s), 10.52(1H, s), 12.17(1H, brs).

Example 93 Preparation of the Compound of Compound No. 93

Using 5-bromosalicylic acid and 3-methoxy-5-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 58.8%.

¹H-NMR(DMSO-d₆): δ 3.85(3H, s), 6.98(1H, d, J=8.7 Hz), 7.03(1H, s),7.57-7.61(2H, m), 7.77(1H, s), 8.00(1H, d, J=2.4 Hz), 10.57(1H, s),11.56(1H, s).

Example 94 Preparation of the Compound of Compound No. 94

Using 5-bromosalicylic acid and 2-methoxy-5-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 71.3%.

¹H-NMR(DMSO-d₆): δ 3.99(3H, s), 7.03(1H, d, J=9.0 Hz), 7.30(1H, d, J=8.7Hz), 7.47-7.51(1H, m), 7.61(1H, dd, J=9.0, 2.4 Hz), 8.10(1H, d, J=2.4Hz), 8.82(1H, d, J=2.1 Hz) 11.03(1H, s), 12.19(1H, s).

Example 95 Preparation of the Compound of Compound No. 95

Using 5-chlorosalicylic acid and 2-methoxy-5-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 83.4%.

¹H-NMR(DMSO-d₆): δ 4.00(3H, s), 7.08(1H, d, J=9.0 Hz), 7.30(1H, d, J=8.7Hz), 7.47-7.52(2H, m), 7.97(1H, d, J=2.7 Hz), 8.83(1H, d, J=2.4 Hz),11.05(1H, s), 12.17(1H, s).

Example 96 Preparation of the Compound of Compound No. 96

Using 5-chlorosalicylic acid and2-methylsulfanyl-5-(trifluoromethyl)aniline as the raw materials, thesame operation as the Example 3 gave the title compound.

Yield: 79.2%.

¹H-NMR(DMSO-d₆): δ 2.57(3H, s), 7.07(1H, d, J=8.7 Hz), 7.52(1H, dd,J=8.7, 2.4 Hz), 7.55(1H, dd, J=8.4, 1.5 Hz), 7.63(1H, d, J=8.1 Hz),8.00(1H, d, J=2.4 Hz), 8.48(1H, d, J=1.5 Hz), 10.79(1H, s), 12.26(1H,s).

Example 97 Preparation of the Compound of Compound No. 97

Using 5-bromosalicylic acid and2-(1-pyrrolidinyl)-5-(trifluoromethyl)aniline as the raw materials, thesame operation as the Example 3 gave the title compound.

Yield: 44.5%.

¹H-NMR(DMSO-d₆): δ 1.86-1.91(4H, m), 3.20-3.26(4H, m), 6.99(1H, d, J=8.7Hz), 7.07(1H, d, J=8.7 Hz), 7.43(1H, dd, J=8.7, 2.1 Hz), 7.62(1H, dd,J=8.7, 2.4 Hz), 7.94(1H, d, J=2.1 Hz), 8.17(1H, d, J=2.4 Hz), 10.54(1H,s), 12.21(1H, s).

Example 98 Preparation of the Compound of Compound No. 98

Using 5-bromosalicylic acid and 2-morpholino-5-(trifluoromethyl)anilineas the raw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 65.9%.

¹H-NMR(DMSO-d₆): δ 2.90(4H, dd, J=4.5, 4.2 Hz), 3.84(4H, dd, J=4.8, 4.2Hz), 7.09(1H, d, J=8.4 Hz), 7.48(2H, s), 7.61(1H, dd, J=8.4, 2.7 Hz),8.13(1H, d, J=2.7 Hz), 8.90(1H, s), 11.21(1H, s), 12.04(1H, s).

Example 99 Preparation of the Compound of Compound No. 99

Using 5-nitrosalicylic acid and 2-chloro-5-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 31.1%.

¹H-NMR(DMSO-d₆): δ 6.98(1H, d, J=9.3 Hz), 7.52(1H, dd, J=8.4, 2.1 Hz),7.81(1H, d, J=8.4 Hz), 8.21(1H, dd, J=9.0, 3.3 Hz), 8.82(1H, d, J=3.0Hz), 8.93(1H, d, J=2.4 Hz), 12.18(1H, s).

Example 100 Preparation of the Compound of Compound No. 100

Using 5-methylsalicylic acid and 2-chloro-5-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 15.8%.

¹H-NMR(CDCl₃): δ 2.36(3H, s), 6.95(1H, d, J=8.1 Hz), 7.26-7.31(2H, m),7.37(1H, dd, J=8.4, 1.8 Hz), 7.56(1H, d, J=8.4 Hz), 8.65(1H, brs),8.80(1H, d, J=1.8 Hz), 11.33(1H, brs).

Example 101 Preparation of the Compound of Compound No. 101

Using 5-methoxysalicylic acid and 2-chloro-5-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 56.4%.

¹H-NMR(DMSO-d₆): δ 3.77(3H, s), 6.91(1H, d, J=9.0 Hz), 7.07(1H, dd,J=8.7, 3.0 Hz), 7.20(1H, t, J=1.8 Hz), 7.52-7.54(3H, m), 10.33(1H, s),11.44(1H, s).

Example 102 Preparation of the Compound of Compound No. 102

Using 5-methylsalicylic acid and 2-methyl-5-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 14.2%, white solid.

¹H-NMR(DMSO-d₆): δ 2.29(3H, s), 2.38(3H, s), 6.94(1H, d, J=8.4 Hz),7.27(1H, ddd, J=8.4, 2.4, 0.6 Hz), 7.44(1H, dd, J=8.1, 1.5 Hz), 7.52(1H,d, J=7.8 Hz), 7.84(1H, d, J=2.4 Hz), 8.46(1H, d, J=1.5 Hz), 10.55(1H,s), 11.72(1H, s).

Example 103 Preparation of the Compound of Compound No. 103

Using 5-methylsalicylic acid and 2-methoxy-5-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 77.9%.

¹H-NMR(CDCl₃): δ 2.35(3H, s), 4.02(3H, s), 6.93(1H, d, J=9.0 Hz),6.98(1H, d, J=8.4 Hz), 7.25-7.28(2H, m), 7.36(1H, ddd, J=8.4, 2.1, 0.9Hz), 8.65(1H, brs), 8.73(1H, d, J=2.1 Hz), 11.69(1H, s).

Example 104 Preparation of the Compound of Compound No. 104

Using 5-chlorosalicylic acid and 3-bromo-5-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 37.1%.

¹H-NMR(DMSO-d₆): δ 7.03(1H, d, J=9.3 Hz), 7.48(1H, dd, J=8.7, 2.4 Hz),7.72(1H, s), 7.84(1H, d, J=2.7 Hz), 8.16(1H, s), 8.28(1H, s), 10.69(1H,s), 11.42(1H, s).

Example 105 Preparation of the Compound of Compound No. 105

Using 5-chlorosalicylic acid and 3-methoxy-5-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 68.0%.

¹H-NMR(DMSO-d₆): δ 3.85(3H, s), 7.02(1H, s), 7.03(1H, d, J=8.7 Hz),7.48(1H, dd, J=8.7, 2.7 Hz), 7.61(1H, s), 7.77(1H, s), 7.88(1H, d, J=2.7Hz), 10.57(1H, s), 11.53(1H, s).

Example 106 Preparation of the Compound of Compound No. 106

Using 5-chlorosalicylic acid and 2-morpholino-5-(trifluoromethyl)anilineas the raw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 64.8%.

¹H-NMR(DMSO-d₆): δ 2.90(4H, m), 3.84(4H, m), 7.15(1H, d, J=9.0 Hz),7.48(2H, s), 7.50(1H, dd, J=9.0, 2.7 Hz), 8.00(1H, d, J=2.7 Hz),8.91(1H, s), 11.24(1H, s), 12.05(1H, s).

Example 107 Preparation of the Compound of Compound No. 107

Using 5-chlorosalicylic acid and 2-bromo-5-(trifluoromethyl)aniline asthe raw material, the same operation as the Example 3 gave the titlecompound.

Yield: 59.2%.

¹H-NMR(DMSO-d₆): δ 7.10(1H, d, J=8.7 Hz), 7.48(1H, dd, J=8.4, 2.1 Hz),7.53(1H, dd, J=8.7, 3.0 Hz), 7.97-7.99(2H, m), 8.81(1H, d, J=2.1 Hz),11.03(1H, s), 12.38(1H, s).

Example 108 Preparation of the Compound of Compound No. 108

Using 5-chlorosalicylic acid and 3-amino-5-(trifluoromethyl)benzoic acidmethyl ester as the raw materials, the same operation as the Example 3gave the title compound.

Yield: 67.0%.

¹H-NMR(DMSO-d₆): δ 3.91(3H, s), 7.02(1H, d, J=9.3 Hz), 7.43(1H, dd,J=9.0, 2.4 Hz), 7.57(1H, d, J=2.4 Hz), 8.13(1H, s), 8.23(1H, s),8.29(1H, s), 8.36(1H, s), 11.52(1H, s).

Example 109 Preparation of the Compound of Compound No. 109

2N Aqueous sodium hydroxide (0.6 mL) was added to a suspension of5-chloro-2-hydroxy-N-[3-methoxycarbonyl-5-(trifluoromethyl)phenyl]benzamide(Compound No. 108; 105 mg, 0.281 mmol) in methanol (2.5 mL), and themixture was stirred at room temperature for 3 hours. Water was added tothe reaction mixture and it was washed with ethyl acetate. After thewater layer was acidified by addition of diluted hydrochloric acid, itwas extracted with ethyl acetate. After the ethyl acetate layer waswashed successively with water and brine, dried over anhydrous sodiumsulfate, the residue obtained by evaporation of the solvent underreduced pressure was crystallized by isopropyl ether to give the titlecompound (100 mg, 99.0%) as a white solid.

¹H-NMR(DMSO-d₆): δ 7.04(1H, d, J=9.0 Hz), 7.49(1H, dd, J=8.7, 2.7 Hz),7.91(1H, d, J=2.7 Hz), 7.93(1H, s), 8.43(1H, s), 8.59(1H, s), 10.78(1H,s), 11.48(1H, s).

Example 110 Preparation of the Compound of Compound No. 110

Using 5-chlorosalicylic acid and2-(2-naphthyloxy)-5-(trifluoromethyl)aniline as the raw materials, thesame operation as the Example 3 gave the title compound.

Yield: 89.6%.

¹H-NMR(CDCl₃): δ 6.94(1H, d, J=9.6 Hz), 6.98(1H, d, J=9.2 Hz),7.25-7.41(4H, m), 7.48-7.57(3H, m), 7.81(1H, d, J=6.9 Hz), 7.88(1H, d,J=6.9 Hz), 7.95(1H, d, J=8.9 Hz), 8.72(1H, s), 8.83(1H, d, J=2.0 Hz),11.70(1H, s).

Example 111 Preparation of the Compound of Compound No. 111

Using 5-chlorosalicylic acid and2-(2,4-dichlorophenoxy)-5-(trifluoromethyl)aniline as the raw materials,the same operation as the Example 3 gave the title compound.

Yield: 4.7%.

¹H-NMR(CDCl₃): δ 6.78(1H, d, J=8.9 Hz), 7.02(1H, d, J=8.6 Hz), 7.16(1H,d, J=8.6 Hz), 7.33-7.38(3H, m), 7.42(1H, dd, J=8.6, 2.6 Hz), 7.49(1H, d,J=2.6 Hz) 7.58(1H, d, J=2.3 Hz), 8.66(1H, brs,), 8.82(1H, d, J=2.0 Hz),11.65(1H, s).

Example 112 Preparation of the Compound of Compound No. 112

Using 5-chlorosalicylic acid and2-[(4-trifluoromethyl)piperidino]-5-(trifluoromethyl)aniline as the rawmaterials, the same operation as the Example 3 gave the title compound.

Yield: 60.5%.

¹H-NMR(CDCl₃): δ 1.85-2.05(2H, m), 2.15(2H, d, J=10.9 Hz), 2.28(1H, m),2.82(2H, t, J=11.0 Hz), 3.16(2H, d, J=12.2 Hz), 7.02(1H, d, J=8.9 Hz),7.31(1H, d, J=8.3 Hz), 7.42(2H, m), 7.50(1H, d, J=2.6 Hz), 8.75(1H, s),9.60(1H, s), 11.94(1H, s)

Example 113 Preparation of the Compound of Compound No. 113

Using 5-chlorosalicylic acid and2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)aniline as the rawmaterials, the same operation as the Example 3 gave the title compound.

Yield: 94.5%.

¹H-NMR(CDCl₃): δ 4.58(2H, q, J=7.9 Hz), 6.99-7.05(2H, m), 7.41-7.50(3H,m), 8.63(1H, brs), 8.79(1H, d, J=2.0 Hz), 11.59(1H, s).

Example 114 Preparation of the Compound of Compound No. 114

Using 5-chlorosalicylic acid and2-(2-methoxyphenoxy)-5-(trifluoromethyl)aniline as the raw materials,the same operation as the Example 3 gave the title compound.

Yield: 80.6%.

¹H-NMR(DMSO-d₆): δ 3.74(3H, s), 6.70(1H, d, J=8.4 Hz), 7.02(1H, d, J=8.7Hz), 7.07(1H, dd, J=1.5, 7.8 Hz), 7.24-7.39(4H, m), 7.49(1H, dd, J=3.0,8.7 Hz), 8.00(1H, d, J=3.0 Hz), 8.92(1H, d, J=2.1 Hz), 11.36(1H, s),12.18(1H, s).

Example 115 Preparation of the Compound of Compound No. 115

Using 5-chlorosalicylic acid and2-(4-chloro-3,5-dimethylphenoxy)-5-(trifluoromethyl)aniline as the rawmaterials, the same operation as the Example 3 gave the title compound.

Yield: 91.5%.

¹H-NMR(DMSO-d₆): δ 2.34(6H, s), 7.03(1H, d, J=8.8 Hz), 7.05(1H, d, J=8.1Hz), 7.11(2H, s), 7.43-7.47(1H, m), 7.48(1H, dd, J=2.9, 8.8 Hz),7.97(1H, d, J=2.6 Hz), 8.94(1H, d, J=2.2 Hz), 11.25(1H, s), 12.12(1H,s).

Example 116 Preparation of the Compound of Compound No. 116

Using 5-chlorosalicylic acid and 2-piperidino-5-(trifluoromethyl)anilineas the raw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 73.7%.

¹H-NMR(CDCl₃): δ 1.68-1.72(2H, m), 1.80-1.88(4H, m), 2.89(4H, t, J=5.2Hz), 7.01(1H, d, J=8.7 Hz), 7.31(1H, d, J=8.4 Hz), 7.39-7.43(2H, m),7.55(1H, d, J=2.4 Hz), 8.73(1H, d, J=1.8 Hz), 9.71(1H, s), 12.05(1H, s)

Example 117 Preparation of the Compound of Compound No. 117

Using 5-chlorosalicylic acid and2-(4-methylphenoxy)-5-(trifluoromethyl)aniline as the raw materials, thesame operation as the Example 3 gave the title compound.

Yield: 67.3%.

¹H-NMR(DMSO-d₆): δ 2.33(3H, s), 6.93(1H, d, J=8.8 Hz), 7.03(1H, dd,J=0.5, 8.8 Hz), 7.12(2H, d, J=8.2 Hz), 7.29(2H, d, J=8.5 Hz), 7.43(1H,dd, J=2.0, 8.6 Hz), 7.48(1H, ddd, J=0.8, 2.7, 8.8 Hz), 7.98(1H, dd,J=0.8, 2.7 Hz), 8.94(1H, d, J=2.2 Hz), 11.29(1H, s), 12.15(1H, s).

Example 118 Preparation of the Compound of Compound No. 118

Using 5-chlorosalicylic acid and2-(4-chlorophenoxy)-5-(trifluoromethyl)aniline as the raw materials, thesame operation as the Example 3 gave the title compound.

Yield: 74.5%.

¹H-NMR(DMSO-d₆): δ 7.01(1H, d, J=8.8 Hz), 7.06(1H, d, J=8.5 Hz),7.22(1H, d, J=8.5 Hz), 7.43-7.48(2H, m), 7.50(2H, d, J=8.2 Hz), 7.94(1H,dd, J=0.5, 2.7 Hz), 8.92(1H, d, J=2.2 Hz), 11.20(1H, s), 12.10(1H, s).

Example 119 Preparation of the Compound of Compound No. 119

Using 5-chloro-2-hydroxynicotinic acid and2-chloro-5-(trifluoromethyl)aniline as the raw materials, the sameoperation as the Example 75 gave the title compound.

Yield: 42.9%.

¹H-NMR(DMSO-d₆): δ 7.52(1H, dd, J=8.4, 2.1 Hz), 7.81(1H, d, J=8.4 Hz),8.16(1H, s), 8.39(1H, d, J=2.7 Hz), 8.96(1H, d, J=2.1 Hz), 12.76(1H, s),13.23(1H, s).

Example 120 Preparation of the Compound of Compound No. 120

Using O-acetylsalicyloyl chloride and 3,5-dichloroaniline as the rawmaterials, the same operation as the Example 1 gave the title compound.

Yield: 73.5%.

mp 167-168° C.

¹H-NMR(CDCl₃): δ 2.35(3H, s), 7.14-7.18(2H, m), 7.35-7.40(1H, m),7.52-7.57(3H, m), 7.81(1H, dd, J=7.8, 1.8 Hz), 8.05(1H, brs).

Example 121 Preparation of the Compound of Compound No. 121

Using 2-acetoxy-N-(3,5-dichlorophenyl)benzamide (Compound No. 121) asthe raw material, the same operation as the Example 2 gave the titlecompound.

Yield: 60.3%.

mp 218-219° C.

¹H-NMR(DMSO-d₆): δ 6.95-7.02(2H, m), 7.35-7.36(1H, m), 7.42-7.47(1H, m),7.83-7.87(3H, m), 10.54(1H, s), 11.35(1H, s).

Example 122 Preparation of the Compound of Compound No. 122

Using 5-chlorosalicylic acid and 2,5-dichloroaniline as the rawmaterials, the same operation as the Example 3 gave the title compound.

Yield: 10.8%.

¹H-NMR(DMSO-d₆): δ 7.08(1H, d, J=9.0 Hz), 7.24-7.28(1H, m),7.50-7.54(1H, m), 7.61(1H, dd, J=9.0, 3.0 Hz), 7.97(1H, d, J=2.7 Hz),8.58(1H, d, J=2.4 Hz), 11.02(1H, s), 12.35(1H, brs).

Example 123 Preparation of the Compound of Compound No. 123

Using 5-bromosalicylic acid and 3,5-difluoroaniline as the rawmaterials, the same operation as the Example 3 gave the title compound.

Yield: 36.3%.

mp 259-261° C.

¹H-NMR(DMSO-d₆): δ 6.96-7.04(2H, m), 7.45-7.54(2H, m), 7.58(1H, dd,J=8.7, 2.7 Hz), 7.94(1H, d, J=2.7 Hz), 10.60(1H, s) 11.48(1H, s).

Example 124 Preparation of the Compound of Compound No. 124

Using 5-fluorosalicylic acid and 3,5-dichloroaniline as the rawmaterials, the same operation as the Example 3 gave the title compound.

Yield: 33.3%.

mp 258-260° C.

¹H-NMR(DMSO-d₆): δ 7.00-7.05(1H, m), 7.28-7.37(2H, m), 7.63(1H, dd,J=9.3, 3.3 Hz), 7.84(2H, d, J=2.1 Hz), 10.56(1H, s), 11.23(1H, s).

Example 125 Preparation of the Compound of Compound No. 125

Using 5-chlorosalicylic acid and 3,5-dichloroaniline as the rawmaterials, the same operation as the Example 3 gave the title compound.

Yield: 41.2%.

¹H-NMR(DMSO-d₆): δ 7.03(1H, d, J=9.0 Hz), 7.36-7.37(1H, m), 7.48(1H, dd,J=8.7, 2.7 Hz), 7.83-7.84(3H, m), 10.56(1H, s), 11.44(1H, s).

Example 126 Preparation of the Compound of Compound No. 126

Using 5-bromosalicylic acid and 3,5-dichloroaniline as the rawmaterials, the same operation as the Example 3 gave the title compound.

Yield: 61.6%.

mp 243-244° C.

¹H-NMR(DMSO-d₆): δ 6.98(1H, d, J=8.7 Hz), 7.36-7.37(1H, m), 7.59(1H, dd,J=9.0, 2.4 Hz), 7.83(2H, d, J=1.8 Hz), 7.95(1H, d, J=2.4 Hz), 10.56(1H,s), 11.46(1H, s).

Example 127 Preparation of the Compound of Compound No. 127

Using 5-iodosalicylic acid and 3,5-dichloroaniline as the raw materials,the same operation as the Example 3 gave the title compound.

Yield: 65.4%.

mp 244-245° C.

¹H-NMR(DMSO-d₆): δ 6.84(1H, d, J=9.0 Hz), 7.35-7.37(1H, m), 7.72(1H, dd,J=9.0, 2.1 Hz), 7.83(2H, d, J=1.8 Hz), 8.09(1H, d, J=2.1 Hz), 10.55(1H,s), 11.45(1H, s).

Example 128 Preparation of the Compound of Compound No. 128

Using 3,5-dibromosalicylic acid and 3,5-dichloroaniline as the rawmaterials, the same operation as the Example 3 gave the title compound.

Yield: 44.2%.

mp 181-182° C.

¹H-NMR(DMSO-d₆): δ 7.42-7.43(1H, m), 7.80(2H, d, J=1.8 Hz), 8.03(1H, d,J=2.1 Hz), 8.17(1H, d, J=2.1 Hz), 10.82(1H, s).

Example 129 Preparation of the Compound of Compound No. 129

Using 4-chlorosalicylic acid and 3,5-dichloroaniline as the rawmaterials, the same operation as the Example 3 gave the title compound.

Yield: 57.2%.

mp 255-256° C.

¹H-NMR(DMSO-d₆): δ 7.03-7.06(2H, m), 7.34-7.36(1H, m), 7.82-7.85(3H,m),10.51(1H, s), 11.70(1H, brs).

Example 130 Preparation of the Compound of Compound No. 130

Using 5-nitrosalicylic acid and 3,5-dichloroaniline as the rawmaterials, the same operation as the Example 3 gave the title compound.

Yield: 83.1%.

mp 232-233° C.

¹H-NMR(DMSO-d₆): δ 7.16(1H, d, J=9.6 Hz), 7.37-7.39(1H, m), 7.84(1H, d,J=2.1 Hz), 8.29(1H, dd, J=9.0, 3.0 Hz), 8.65(1H, d, J=3.0 Hz), 10.83(1H,s).

Example 131 Preparation of the Compound of Compound No. 131

Using 5-methylsalicylic acid and 3,5-dichloroaniline as the rawmaterials, the same operation as the Example 3 gave the title compound.

Yield: 71.0%.

mp 216-217° C.

¹H-NMR(DMSO-d₆): δ 2.28(3H, s), 6.90(1H, d, J=8.4 Hz), 7.26(1H, dd,J=8.7, 1.8 Hz), 7.34-7.36(1H, m), 7.67(1H, d, J=1.5 Hz), 7.85(2H, d,J=1.8 Hz), 10.52(1H, s), 11.15(1H, s).

Example 132 Preparation of the Compound of Compound No. 132

Using 5-methoxysalicylic acid and 3,5-dichloroaniline as the rawmaterials, the same operation as the Example 3 gave the title compound.

Yield: 29.8%.

mp 230-232° C.

¹H-NMR(DMSO-d₆): δ 3.76(3H, s), 6.95(1H, d, J=8.7 Hz), 7.08(1H, dd,J=9.0, 3.0 Hz), 7.35-7.36(1H, m), 7.40(1H, d, J=3.0 Hz), 7.85(2H, d,J=1.5 Hz), 10.55(1H, s), 10.95(1H, s).

Example 133 Preparation of the Compound of Compound No. 133

Using 5-bromosalicylic acid and 3,5-dinitroaniline as the raw materials,the same operation as the Example 3 gave the title compound.

Yield: 32.2%.

mp 258-260° C.

¹H-NMR(DMSO-d₆): δ 6.98-7.02(1H, m), 7.59-7.63(1H, m), 7.96-7.97(1H, m),8.56-8.58(1H, m), 9.03-9.05(2H, m), 11.04(1H, s), 11.39(1H, brs).

Example 134 Preparation of the Compound of Compound No. 134

Using 5-chlorosalicylic acid and 2,5-bis[(1,1-dimethyl)ethyl]aniline asthe raw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 75.7%.

¹H-NMR(DMSO-d₆): δ 1.27(9H, s), 1.33(9H, s), 7.04(1H, d, J=9.0 Hz),7.26(1H, dd, J=8.4, 2.1 Hz), 7.35-7.38(2H, m), 7.49(1H, dd, J=8.7, 2.7Hz), 8.07(1H, d, J=2.4 Hz), 10.22(1H, s), 12.38(1H, brs).

Example 135 Preparation of the Compound of Compound No. 135

Using 5-chlorosalicylic acid and5-[(1,1-dimethyl)ethyl]-2-methoxyaniline as the raw materials, the sameoperation as the Example 3 gave the title compound.

Yield: 89.5%.

¹H-NMR(DMSO-d₆): δ 1.28(9H, s), 3.33(3H, s), 7.01(1H, d, J=8.7 Hz),7.05(1H, d, J=9.0 Hz), 7.11(1H, dd, J=8.7, 2.4 Hz), 7.47(1H, dd, J=9.0,3.0 Hz), 7.99(1H, d, J=3.0 Hz), 8.49(1H, d, J=2.4 Hz), 10.78(1H, s),12.03(1H, s).

Example 136 Preparation of the Compound of Compound No. 136

Using5-chloro-N-{5-[(1,1-dimethyl)ethyl]-2-methoxyphenyl}-2-hydroxybenzamide(Compound No. 135) and acetyl chloride as the raw materials, the sameoperation as the Example 5 gave the title compound.

Yield: 87.5%.

¹H-NMR(CDCl₃): δ 1.35(9H, s), 2.37(3H, s), 3.91(3H, s), 6.86(1H, d,J=8.7 Hz), 7.12(1H, dd, J=8.7, 2.4 Hz), 7.13(1H, d, J=9.0 Hz), 7.47(1H,dd, J=9.0, 2.4 Hz), 8.02(1H, d, J=2.7 Hz), 8.66(1H, d, J=2.4 Hz),8.93(1H, s).

Example 137 Preparation of the Compound of Compound No. 137

Using 5-bromosalicylic acid and 3,5-dimethylaniline as the rawmaterials, the same operation as the Example 3 gave the title compound.

Yield: 58.1%.

mp 188-190° C.

¹H-NMR(DMSO-d₆): δ 2.28(6H, s), 6.80(1H, s), 6.96(1H, d, J=8.7 Hz),7.33(2H, s), 7.58(1H, dd, J=9.0, 2.4 Hz), 8.10(1H, d, J=2.4 Hz),10.29(1H, s), 11.93(1H, brs).

Example 138 Preparation of the Compound of Compound No. 138

Using 5-chlorosalicylic acid and 3,5-bis[(1,1-dimethyl)ethyl]aniline asthe raw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 34.1%.

¹H-NMR(CDCl₃): δ 1.26(18H, s), 6.99(1H, d, J=8.7 Hz), 7.29(1H, t, J=1.8Hz), 7.39(1, dd, J=9.0, 2.4 Hz), 7.41(2H, d, J=1.5 Hz), 7.51(1H, d,J=2.1 Hz), 7.81(1H, brs), 12.01(1H, s).

Example 139 Preparation of the Compound of Compound No. 139

Using N-{3,5-bis[(1,1-dimethyl)ethyl]phenyl}-5-chloro-2-hydroxybenzamide(Compound No. 138) and acetyl chloride as the raw materials, the sameoperation as the Example 5 gave the title compound.

Yield: 66.1%.

¹H-NMR(CDCl₃): δ 1.34(18H, s), 2.36(3H, s), 7.12(1H, d, J=8.4 Hz),7.25(1H, d, J=1.5 Hz), 7.44(2H, d, J=1.2 Hz), 7.47(1H, dd, J=8.7, 2.7Hz), 7.87(1H, d, J=2.4 Hz), 7.98(1H, s).

Example 140 Preparation of the Compound of Compound No. 140

Using 5-bromosalicylic acid and 3,5-bis[(1,1-dimethyl)ethyl]aniline asthe raw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 45.2%.

¹H-NMR(DMSO-d₆): δ 1.30(18H, s), 6.95(1H, d, J=8.7 Hz), 7.20(1H, t,J=1.5 Hz), 7.56(2H, d, J=1.5 Hz), 7.58(1H, dd, J=8.7, 2.4 Hz), 8.12(1H,d, J=2.7 Hz), 10.39(1H, s), 11.98(1H, s).

Example 141 Preparation of the Compound of Compound No. 141

Using 5-chlorosalicylic acid and 3-amino-4-methoxybiphenyl as the rawmaterials, the same operation as the Example 3 gave the title compound.

Yield: 37.0%.

¹H-NMR(DMSO-d₆): δ 3.95(3H, s), 7.08(1H, d, J=8.7 Hz), 7.20(1H, d, J=8.4Hz), 7.34(1H, t, J=7.2 Hz), 7.40-7.50(4H, m), 7.62(1H, d, J=8.7 Hz),8.00(1H, d, J=3.0 Hz), 8.77(1H, d, J=2.1 Hz), 10.92(1H, s), 12.09(1H,s).

Example 142 Preparation of the Compound of Compound No. 142

Using 5-bromosalicylic acid and 2,5-dimethoxyaniline as the rawmaterials, the same operation as the Example 3 gave the title compound.

Yield: 39.7%.

¹H-NMR(DMSO-d₆): δ 3.72(3H, s), 3.84(3H, s), 6.66(1H, ddd, J=9.0, 3.0,0.6 Hz), 6.99-7.03(2H, m), 7.58(1H, ddd, J=9.0, 2.7, 0.6 Hz), 8.10(1H,dd, J=2.4, 0.6 Hz), 8.12(1H, d, J=3.0 Hz), 10.87(1H, s), 12.08(1H, s).

Example 143 Preparation of the Compound of Compound No. 143

Using 5-bromosalicylic acid and 3,5-dimethoxyaniline as the rawmaterials, the same operation as the Example 3 gave the title compound.

Yield: 40.3%.

mp 207-209° C.

¹H-NMR(DMSO-d₆): δ 3.75(6H, s), 6.30-6.32(1H, m), 6.94-6.97(3H, m),7.57(1H, dd, J=8.7, 2.4 Hz), 8.04(1H, d, J=2.4 Hz), 10.32(1H, s),11.78(1H, s).

Example 144 Preparation of the Compound of Compound No. 144

Using 5-bromosalicylic acid and 5-aminoisophthalic acid dimethyl esteras the raw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 74.1%.

mp 254-256° C.

¹H-NMR(DMSO-d₆): δ 3.92(6H, s), 6.97(1H, d, J=9.0 Hz), 7.60(1H, dd,J=9.0, 2.4 Hz), 8.06(1H, d, J=2.4 Hz), 8.24-8.25(1H, m), 8.62(2H, m),10.71(1H, s), 11.57(1H, s).

Example 145 Preparation of the Compound of Compound No. 145

Using 5-methylsalicylic acid and 2,5-bis[(1,1-dimethyl)ethyl]aniline asthe raw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 61.1%.

¹H-NMR(DMSO-d₆): δ 1.27(9H, s), 1.33(9H, s), 2.28(3H, s), 6.89(1H, d,J=8.1 Hz), 7.24(1H, d, J=2.1 Hz), 7.27(1H, d, J=2.1 Hz), 7.32(1H, d,J=2.4 Hz), 7.37(1H, d, J=8.4 Hz), 7.88(1H, d, J=1.5 Hz), 10.15(1H, s),11.98(1H, brs).

Example 146 Preparation of the Compound of Compound No. 146

Using 5-nitrosalicylic acid and 3,5-bis[(1,1-dimethyl)ethyl]aniline asthe raw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 46.7%.

¹H-NMR(CDCl₃): δ 1.37(18H, s), 7.13(1H, d, J=9.3 Hz), 7.32(1H, t, J=1.8Hz), 7.46(2H, d, J=1.8 Hz), 8.07(1H, s), 8.33(1H, dd, J=9.3, 2.1 Hz),8.59(1H, d, J=2.4 Hz), 13.14(1H, s).

Example 147 Preparation of the Compound of Compound No. 147

Using 5-methylsalicylic acid and 3,5-bis[(1,1-dimethyl)ethyl]aniline asthe raw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 16.3%.

¹H-NMR(CDCl₃): δ 1.35(18H, s), 2.35(3H, s), 6.94(1H, d, H=8.4 Hz),7.23-7.28(2H, m), 7.31(1H, s), 7.42(1H, d, J=1.8 Hz), 7.88(1H, s),11.86(1H, s).

Example 148 Preparation of the Compound of Compound No. 148

Using 5-methoxysalicylic acid and 3,5-bis[(1,1-dimethyl)ethyl]aniline asthe raw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 12.7%.

¹H-NMR(DMSO-d₆): δ 1.30(18H, s), 3.77(3H, s), 6.91(1H, d, J=9.0 Hz),7.07(1H, dd, J=8.7, 3.0 Hz), 7.19-7.20(1H, m), 7.52-7.54(3H, m),10.33(1H, s), 11.44(1H, s).

Example 149 Preparation of the Compound of Compound No. 149

Using 5-methylsalicylic acid and5-[(1,1-dimethyl)ethyl]-2-methoxyaniline as the raw materials, the sameoperation as the Example 3 gave the title compound.

Yield: 84.7%.

¹H-NMR(CDCl₃): δ 1.35(9H, s), 2.34(3H, s), 3.93(3H, s), 6.86(1H, d,J=8.7 Hz), 6.93(1H, d, J=8.4 Hz), 7.12(1H, dd, J=8.7, 2.4 Hz), 7.24(1H,dd, J=8.4, 1.8 Hz), 7.27(1H, brs), 8.48(1H, d, J=2.4 Hz), 8.61(1H, brs),11.95(1H, s).

Example 150 Preparation of the Compound of Compound No. 150

Using 5-bromo-2-hydroxy-N-[3,5-bis(methoxycarbonyl)phenyl]benzamide(Compound No. 144) as the raw material, the same operation as theExample 109 gave the title compound.

Yield: 89.0%.

¹H-NMR(DMSO-d₆): δ 6.98(1H, d, J=8.7 Hz), 7.60(1H, dd, J=8.7, 2.4 Hz),7.24(1H, dd, J=8.7, 2.7 Hz), 8.08(1H, d, J=2.7 Hz), 8.24(1H, t, J=1.5Hz), 8.57(2H, d, J=1.2 Hz), 10.67(1H, s), 11.64(1H, s).

Example 151 Preparation of the Compound of Compound No. 151

Using 5-chlorosalicylic acid and 2-methyl-5-[(1-methyl)ethyl]aniline asthe raw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 19.1%.

¹H-NMR(CDCl₃): δ 1.26(6H, d, J=6.9 Hz), 2.30(3H, s), 2.87-2.96(1H, m),7.00(1H, d, J=8.7 Hz), 7.08(1H, dd, J=7.8, 1.8 Hz), 7.20(1H, d, J=7.8Hz), 7.40(1H, dd, J=8.7, 2.4 Hz), 7.49(1H, d, J=2.7 Hz), 7.50(1H, s),7.71(1H, s), 11.99(1H, s).

Example 152 Preparation of the Compound of Compound No. 152

Using 5-chlorosalicylic acid and 2,5-diethoxyaniline as the rawmaterials, the same operation as the Example 3 gave the title compound.

Yield: 59.2%.

¹H-NMR(DMSO-d₆): δ 1.32(3H, t, J=6.9 Hz), 1.41(3H, t, J=6.9 Hz),3.97(2H, q, J=6.9 Hz), 4.06(2H, q, J=6.9 Hz), 6.61(1H, dd, J=9.0, 3.0Hz), 6.98(1H, d, J=8.7 Hz), 7.10(1H, d, J=8.7 Hz), 7.48(1H, dd, J=8.7,2.7 Hz), 7.97(1H, d, J=2.7 Hz), 8.16(1H, d, J=3.0 Hz), 10.96(1H, s),11.91(1H, s).

Example 153 Preparation of the Compound of Compound No. 153

Using 5-chlorosalicylic acid and 2,5-dimethylaniline as the rawmaterials, the same operation as the Example 3 gave the title compound.

Yield: 90.5%.

¹H-NMR(CDCl₃): δ 2.28(3H, s), 2.35(3H, s), 6.99(1H, d, J=8.8 Hz),7.02(1H, brs), 7.15(1H, d, J=7.7 Hz), 7.40(1H, dd, J=8.8, 2.5 Hz),7.45(1H, brs), 7.49(1H, d, J=2.5 Hz) 7.70(1H, br), 11.96(1H, brs).

Example 154 Preparation of the Compound of Compound No. 154

Using 5-chlorosalicylic acid and 5-chloro-2-cyanoaniline as the rawmaterials, the same operation as the Example 3 gave the title compound.

Yield: 90.0%.

¹H-NMR(DMSO-d₆): δ 7.09(1H, d, J=9.0 Hz), 7.53(1H, dd, J=8.7, 3.0 Hz),7.82(1H, dd, J=8.7, 2.4 Hz), 7.95(1H, d, J=3.0 Hz), 8.07(1H, d, J=2.4Hz), 8.36(1H, d, J=9.0 Hz), 11.11(1H, s), 12.36(1H, s).

Example 155 Preparation of the Compound of Compound No. 155

Using 5-chlorosalicylic acid and5-(N,N-diethylsulfamoyl)-2-methoxyaniline as the raw materials, the sameoperation as the Example 3 gave the title compound.

Yield: 44.8%.

¹H-NMR(CDCl₃): δ 1.17(6H, t, J=7.3 Hz), 3.29(4H, q, J=7.3 Hz), 4.05(3H,s), 7.00(2H, dd, J=2.3, 8.9 Hz), 7.41(1H, dd, J=2.3, 8.9 Hz), 7.48(1H,d, J=2.6 Hz), 7.65(1H, dd, J=2.3, 8.6 Hz), 8.56(1H, br.s), 8.84(1H, d,J=2.3 Hz), 11.82(1H, s).

Example 156 Preparation of the Compound of Compound No. 156

Using 5-chlorosalicylic acid and 2-chloro-5-nitroaniline as the rawmaterials, the same operation as the Example 3 gave the title compound.

Yield: 73.3%.

¹H-NMR(CD₃OD): δ 6.98(1H, d, J=8.6 Hz), 7.43(1H, dd, J=2.6, 8.6 Hz),7.74(1H, d, J=8.9 Hz), 7.99(1H, dd, J=3.0, 8.9 Hz), 8.08(1H, d, J=2.6Hz), 9.51(1H, d, J=2.6 Hz)

Example 157 Preparation of the Compound of Compound No. 157

Using 5-chlorosalicylic acid and 5-(N-phenylcarbamoyl)-2-methoxyanilineas the raw material, the same operation as the Example 3 gave the titlecompound.

Yield: 40.3%.

¹H-NMR(DMSO-d₆): δ 3.99(3H, s), 7.09(2H, dd, J=6.6, 6.9 Hz), 7.24(1H, d,J=8.6 Hz), 7.35(2H, dd, 6.9, 7.3 Hz), 7.49(1H, d, J=2.3, 8.9 Hz),7.77(3H, d, J=8.6 Hz), 8.00(1H, s), 8.97(1H, s), 10.17(1H, s), 10.91(1H,s), 12.11(1H, s).

Example 158 Preparation of the Compound of Compound No. 158

Using 5-chlorosalicylic acid and 2,5-dimethoxyaniline as the rawmaterials, the same operation as the Example 3 gave the title compound.

Yield: 73.9%.

¹H-NMR(CDCl₃): δ 3.82(3H, s), 3.93(3H, s), 6.66(1H, dd, J=3.0, 8.9 Hz),6.86(1H, d, J=8.9 Hz), 6.98(1H, d, J=8.9 Hz), 7.39(1H, dd, J=2.6, 8.9Hz), 7.47(1H, d, J=2.6 Hz), 8.08(1H, d, J=3.0 Hz), 8.60(1H, br.s),12.03(1H, s).

Example 159 Preparation of the Compound of Compound No. 159

Using 5-chlorosalicylic acid and 5-acetylamino-2-methoxyaniline as theraw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 16.9%.

¹H-NMR(DMSO-d₆): δ 2.01(3H, s), 3.85(3H, s), 7.03(2H, t, J=9.6 Hz),7.49(2H, dd, J=8.9, 9.2 Hz), 7.96(1H, s), 8.51(1H, s), 9.87(1H, s),10.82(1H, s), 12.03(1H, d, J=4.0 Hz).

Example 160 Preparation of the Compound of Compound No. 160

Using 5-chlorosalicylic acid and 5-methoxy-2-methylaniline as the rawmaterials, the same operation as the Example 3 gave the title compound.

Yield: 100%.

¹H-NMR(CDCl₃): δ 2.29(3H, s), 3.82(3H, s), 6.75(1H, dd, J=2.6, 8.2 Hz),7.00(1H, d, J=8.9 Hz), 7.16(1H, d, J=8.6 Hz), 7.38(1H, d, 2.3 Hz),7.41(1H, dd, J=2.3, 8.9 Hz), 7.48(1H, d, J=2.3 Hz), 7.70(1H, br.s),11.92(1H, s).

Example 161 Preparation of the Compound of Compound No. 161

Using 5-chlorosalicylic acid and 2,5-dibutoxyaniline as the rawmaterials, the same operation as the Example 3 gave the title compound.

Yield: 73.9%.

¹H-NMR(CDCl₃): δ 0.98(3H, t, J=7.2 Hz), 1.05(3H, t, J=7.2 Hz),1.44-1.65(4H, m), 1.72-1.79(2H, m), 1.81-1.91(2H, m), 3.97(2H, t, J=6.3Hz), 4.07(2H, t, J=6.3 Hz), 6.64(1H, dd, J=9.0, 3.0 Hz), 6.85(1H, d,J=9.3 Hz), 6.99(1H, d, J=9.0 Hz), 7.39(1H, dd, J=8.7, 2.4 Hz), 7.44(1H,d, J=2.7 Hz), 8.08(1H, d, J=3.0 Hz), 8.76(1H, s), 12.08(1H, s).

Example 162 Preparation of the Compound of Compound No. 162

Using 5-chlorosalicylic acid and 2,5-diisopentyloxyaniline as the rawmaterials, the same operation as the Example 3 gave the title compound.

Yield: 59.7%.

¹H-NMR(CDCl₃): δ 0.97(6H, d, J=6.6 Hz), 1.03(6H, d, 6.6 Hz),1.64-1.98(6H, m), 3.99(2H, t, J=6.6 Hz), 4.09(2H, t, J=6.3 Hz), 6.63(1H,dd, J=8.7, 3.0 Hz), 6.85(1H, d, J=8.7 Hz), 6.98(1H, d, J=8.7 Hz),7.38(1H, dd, J=9.0, 2.4 Hz), 7.43(1H, d, J=2.7 Hz), 8.09(1H, d, J=3.0Hz), 8.75(1H, s), 12.08(1H, s).

Example 163 Preparation of the Compound of Compound No. 163

Using 5-chlorosalicylic acid and 5-carbamoyl-2-methoxyaniline as the rawmaterials, the same operation as the Example 3 gave the title compound.

Yield: 31.2%.

¹H-NMR(CD₃OD): δ 4.86(3H, s), 6.93(1H, d, J=7.6 Hz), 7.18(1H, d, J=8.6Hz), 7.35(1H, dd, J=3.0, 7.6 Hz), 7.47(1H, dd, J=2.0, 8.6 Hz), 8.00(1H,d, J=3.0 Hz), 8.80(1H, d, J=2.0 Hz).

Example 164 Preparation of the Compound of Compound No. 164

Using 5-chlorosalicylic acid and5-[(1,1-dimethyl)propyl]-2-phenoxyaniline as the raw materials, the sameoperation as the Example 3 gave the title compound.

Yield: 65.2%.

¹H-NMR(CDCl₃): δ 0.69(3H, t, J=7.6 Hz), 1.29(6H, s), 1.64(2H, q, J=7.6Hz), 6.91(1H, dd, J=1.7, 7.6 Hz), 6.96(1H, d, J=8.9 Hz), 7.03(2H, d,J=8.9 Hz), 7.10(1H, dt, J=1.7, 7.6 Hz), 7.16(1H, dt, J=1.7, 7.6 Hz),7.31-7.40(4H, m), 8.42(1H, dd, J=2.0, 7.9 Hz), 8.53(1H, br.s) 11.94(1H,s).

Example 165 Preparation of the Compound of Compound No. 165

Using 5-chlorosalicylic acid and 2-hexyloxy-5-(methylsulfonyl)aniline asthe raw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 33.0%.

¹H-NMR(CDCl₃): δ 0.92(3H, t, J=6.9 Hz), 1.40-1.59(6H, m), 1.90-2.01(2H,m), 3.09(3H, s), 4.22(2H, t, J=6.3 Hz), 7.01(1H, d, J=8.9 Hz), 7.06(1H,d, J=8.6 Hz), 7.40-7.43(2H, m), 7.73(1H, dd, J=8.6, 2.3 Hz), 8.74(1H,brs), 8.99(1H, d, J=2.3 Hz), 11.76(1H, s).

Example 166 Preparation of the Compound of Compound No. 163

Using 5-chlorosalicylic acid and 3′-amino-2,2,4′-trimethylpropiophenoneas the raw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 44.8%.

¹H-NMR(CDCl₃): δ 1.38(9H, s), 2.38(3H, s), 7.01(1H, d, J=8.9 Hz),7.31(1H, d, J=7.9 Hz), 7.42(1H, dd, J=8.9, 2.6 Hz), 7.53(1H, d, J=2.6Hz), 7.57(1H, dd, J=7.9, 2.0 Hz), 7.83(1H, brs), 8.11(1H, d, J=2.0 Hz),11.82(1H, s).

Example 167 Preparation of the Compound of Compound No. 167

Using 5-chlorosalicylic acid and 5-methoxy-2-(1-pyrrolyl)aniline as theraw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 53.4%.

¹H-NMR(CDCl₃): δ 2.46(3H, s), 6.51-6.52(2H, m), 6.82-6.85(3H, m),6.93(1H, d, J=8.9 Hz), 7.06(1H, d, J=7.9 Hz), 7.30(1H, d, J=7.9 Hz),7.32(1H, dd, J=2.3, 8.9 Hz), 7.61(1H, s), 8.29(1H, s), 11.86(1H, br.s).

Example 168 Preparation of the Compound of Compound No. 168

Using 5-chlorosalicylic acid and 5-chloro-2-tosylaniline as the rawmaterials, the same operation as the Example 3 gave the title compound.

Yield: 8.0%.

¹H-NMR(CDCl₃): δ 2.38(3H, s), 7.02(1H, d, J=8.9 Hz), 7.25-7.31(3H, m),7.46(1H, dd, J=2.6, 8.9 Hz), 7.68(2H, d, J=8.6 Hz), 7.74(1H, d, J=2.3Hz), 7.96(1H, d, J=8.6 Hz), 8.56(1H, d, J=2.0 Hz), 10.75(1H, s),11.70(1H, s).

Example 169 Preparation of the Compound of Compound No. 169

Using 5-chlorosalicylic acid and 2-chloro-5-tosylaniline as the rawmaterials, the same operation as the Example 3 gave the title compound.

Yield: 43.5%.

¹H-NMR(CDCl₃): δ 2.38(3H, s), 7.02(1H, d, J=8.9 Hz), 7.27(1H, d, J=7.9Hz), 7.29(1H, dd, J=2.0, 6.6 Hz), 7.46(1H, dd, J=2.3, 8.9 Hz), 7.68(2H,d, J=8.6 Hz), 7.73(2H, d, J=2.3 Hz), 7.97(1H, d, J=8.6 Hz), 8.56(1H, d,J=2.0 Hz), 10.73(1H, s), 11.71(1H, s).

Example 170 Preparation of the Compound of Compound No. 170

Using 5-chlorosalicylic acid and 2-fluoro-5-(methylsulfonyl)aniline asthe raw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 28.8%.

¹H-NMR(CDCl₃): δ 3.12(3H, s), 7.03(1H, d, J=8.9 Hz), 7.38(1H, dd, J=8.6,10.2 Hz), 7.45(1H, dd, J=2.3, 8.9 Hz), 7.53(1H, d, J=2.3 Hz), 7.80(1H,ddd, J=2.3, 4.6, 8.6 Hz), 8.25(1H, s), 8.98(1H, dd, J=2.3, 7.7 Hz),11.33(1H, br.s).

Example 171 Preparation of the Compound of Compound No. 171

Using 5-chlorosalicylic acid and 2-methoxy-5-phenoxyaniline as the rawmaterials, the same operation as the Example 3 gave the title compound.

Yield: 77.0%.

¹H-NMR(CDCl₃): δ 3.98(3H, s), 6.80(1H, d, J=8.8 Hz), 6.90(1H, d, J=8.8Hz), 6.95-7.00(3H, m), 7.04-7.09(1H, m), 7.29-7.35(2H, m), 7.38(1H, dd,J=8.8, 2.6 Hz), 7.47(1H, d, J=2.6 Hz), 8.19(1H, d, J=2.9 Hz), 8.61(1H,brs), 11.92(1H, s).

Example 172 Preparation of the Compound of Compound No. 172

Using 5-chlorosalicylic acid and 3-amino-4-methylbiphenyl as the rawmaterials, the same operation as the Example 3 gave the title compound.

Yield: 47.7%.

¹H-NMR(DMSO-d₆): δ 2.33(3H, s), 7.06(1H, d, J=8.7 Hz), 7.43-7.52(4H, m),7.64-7.67(2H, m), 8.04(1H, d, J=2.7 Hz), 8.19(1H, d, J=1.5 Hz),10.40(1H, s), 12.22(1H, s).

Example 173 Preparation of the Compound of Compound No. 173

Using 5-chlorosalicylic acid and 5-(α,α-dimethylbenzyl)-2-methoxyanilineas the raw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 89.0%.

¹H-NMR(CDCl₃): δ 1.72(6H, s), 3.93(3H, s), 6.83(1H, d, J=8.8 Hz),6.93(1H, dd, J=2.6, 8.8 Hz), 6.96(1H, d, J=9.2 Hz), 7.15-7.20(1H, m),7.25-7.28(4H, m), 7.36(1H, dd, J=2.6, 8.8 Hz), 7.46(1H, d, J=2.6 Hz),8.35(1H, d, J=2.6 Hz), 8.51(1H, s), 12.04(1H, s).

Example 174 Preparation of the Compound of Compound No. 174

Using 5-chlorosalicylic acid and 5-morpholino-2-nitroaniline as the rawmaterials, the same operation as the Example 3 gave the title compound.

Yield: 4.1%.

¹H-NMR(DMSO-d₆): δ 3.46-3.52(4H, m), 3.85-3.94(4H, m), 7.03(1H, d, J=8.8Hz), 7.47(1H, dd, J=2.9, 8.8 Hz), 7.80(1H, dd, J=2.6, 8.8 Hz), 7.82(1H,d, J=2.6 Hz), 7.88(1H, d, J=8.8 Hz), 8.20(1H, d, J=2.2 Hz), 10.70(1H,s), 11.43(1H, s)

Example 175 Preparation of the Compound of Compound No. 175

Using 5-chlorosalicylic acid and 5-fluoro-2-(1-imidazolyl)aniline as theraw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 33.8%.

¹H-NMR(DMSO-d₆): δ 6.99(1H, d, J=8.8 Hz), 7.12-7.19(2H, m),7.42-7.51(3H, m), 7.89(1H, d, J=2.8 Hz), 7.93(1H, d, J=1.1 Hz), 8.34(1H,dd, J=11.4, 2.8 Hz), 10.39(1H, s), 11.76(1H, brs).

Example 176 Preparation of the Compound of Compound No. 176

Using 5-chlorosalicylic acid and 2-butyl-5-nitroaniline as the rawmaterials, the same operation as the Example 3 gave the title compound.

Yield: 15.3%.

¹H-NMR(CDCl₃): δ 0.99(3H, t, J=7.3 Hz), 1.39-1.51(2H, m), 1.59-1.73(2H,m), 2.71-2.79(2H, m), 7.03(1H, d, J=8.9 Hz), 7.41-7.49(3H, m), 7.92(1H,s), 8.07(1H, dd, J=2.3, 8.4 Hz), 8.75(1H, d, J=2.4 Hz), 11.51(1H, s).

Example 177 Preparation of the Compound of Compound No. 177

Using 5-chlorosalicylic acid and5-[(1,1-dimethyl)propyl]-2-hydroxyaniline as the raw materials, the sameoperation as the Example 3 gave the title compound.

Yield: 36.0%.

¹H-NMR(CDCl₃): δ 0.70(3H, t, J=7.4 Hz), 1.28(6H, s), 1.63(2H, q, J=7.4Hz), 6.97(1H, d, J=6.3 Hz), 7.00(1H, d, J=6.6 Hz), 7.08(1H, s), 7.14(1H,dd, J=2.5, 8.6 Hz), 7.36(1H, d, J=2.2 Hz), 7.42(1H, dd, J=2.5, 8.8 Hz),7.57(1H, d, J=2.5 Hz), 8.28(1H, s), 11.44(1H, s).

Example 178 Preparation of the Compound of Compound No. 178

Using 5-chlorosalicylic acid and 2-methoxy-5-methylaniline as the rawmaterials, the same operation as the Example 3 gave the title compound.

Yield: 74.2%.

¹H-NMR(DMSO-d₆): δ 2.27(3H, s), 3.85(3H, s), 6.90(1H, dd, J=9.0, 2.4Hz), 6.98(1H, d, J=9.0 Hz), 7.05(1H, d, J=9.0 Hz), 7.47(1H, dd, J=9.0,3.0 Hz), 7.97(1H, d, J=3.0 Hz), 8.24(1H, d, J=2.4 Hz), 10.79(1H, s),12.03(1H, s).

Example 179 Preparation of the Compound of Compound No. 179

Using 5-chlorosalicylic acid and 2,5-difluoroaniline as the rawmaterials, the same operation as the Example 3 gave the title compound.

Yield: 81.5%.

¹H-NMR(DMSO-d₆): δ 6.98-7.07(1H, m), 7.07(1H, d, J=9.0 Hz),7.37-7.49(1H, m), 7.52(1H, dd, J=8.7, 3.0 Hz), 7.95(1H, d, J=2.7 Hz),8.15-8.22(1H, m), 10.83(1H, s), 12.25(1H, s).

Example 180 Preparation of the Compound of Compound No. 180

Using 5-chlorosalicylic acid and 3,5-difluoroaniline as the rawmaterials, the same operation as the Example 3 gave the title compound.

Yield: 82.0%.

¹H-NMR(DMSO-d₆): δ 7.00(1H, tt, J=9.3, 2.1), 7.03(1H, d, J=9.0 Hz),7.47(1H, dd, J=7.5, 2.7 Hz), 7.49(1H, d, J=2.7 Hz), 7.51(1H, d, J=2.1Hz), 7.82(1H, d, J=3.0 Hz), 10.63(1H, s), 11.43(1H, brs).

Example 181 Preparation of the Compound of Compound No. 181

Using 3-hydroxynaphthalene-2-carboxylic acid and 3,5-dichloroaniline asthe raw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 44.3%.

mp 254-255° C.

¹H-NMR(DMSO-d₆): δ 7.34-7.39(3H, m), 7.49-7.54(1H, m), 7.76-7.79(1H, m),7.89(2H, d, J=1.8 Hz), 7.92(1H, m), 8.39(1H, s), 10.75(1H, s), 11.01(1H,s).

Example 182 Preparation of the Compound of Compound No. 182

Using 2-hydroxynaphthalene-1-carboxylic acid and 3,5-dichloroaniline asthe raw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 51.2%.

mp 246-248° C.

¹H-NMR(DMSO-d₆): δ 7.26(1H, d, J=9.3 Hz), 7.31-7.37(2H, m),7.44-7.50(1H, m), 7.65-7.68(1H, m), 7.85-7.90(4H, m), 10.23(1H, s),10.74(1H, s).

Example 183 The compound of Compound No. 183.

This compound is a commercially available compound. Supplier:Sigma-Aldrich. Catalog code number: S01361-8.

Example 184 Preparation of the Compound of Compound No. 184

Using 5-chloro-2-hydroxynicotinic acid and3,5-bis[(1,1-dimethyl)ethyl]aniline as the raw materials, the sameoperation as the Example 75 gave the title compound.

Yield: 59.1%.

¹H-NMR(DMSO-d₆): δ 1.29(18H, s), 7.18(1H, t, J=1.8 Hz), 7.52(2H. d,J=1.8 Hz), 8.07(1H, d, J=2.4 Hz), 8.35(1H, d, J=3.3 Hz), 11.92(1H, s),13.10(1H, s).

Example 185 Preparation of the Compound of Compound No. 185 (1)2-Amino-4-[(1,1-dimethyl)ethyl]thiazole

A mixture of 1-bromo-3,3-dimethyl-2-butanone (5.03 g, 28.1 mmol),thiourea (2.35 g, 30.9 mmol) and ethanol (30 mL) was refluxed for 1.5hours. After the reaction mixture was cooled to room temperature, it waspoured into saturated aqueous sodium hydrogen carbonate and extractedwith ethyl acetate. After the ethyl acetate layer was washedsuccessively with water and brine, dried over anhydrous sodium sulfate,the residue obtained by evaporation of the solvent under reducedpressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=2:1→1:1) to give the title compound (3.99 g,90.9%) as an yellowish white powder.

¹H-NMR(CDCl₃):d 1.26(9H, s), 4.96(2H, brs), 6.09(1H, s).

When the method described in Example 185(1) is referred in the followingexamples, solvents such as ethanol or the like were used as the reactionsolvent.

(2) 2-Acetoxy-5-bromo-N-{4-[(1,1-dimethyl)ethyl]thiazol-2-yl}benzamide

Using 2-acetoxy-5-bromobenzoic acid and2-amino-4-[(1,1-dimethyl)ethyl]thiazole as the raw materials, the sameoperation as the Example 75 gave the title compound.

Yield: 59.4%.

¹H-NMR(CDCl₃):d 1.31(9H, s), 2.44(3H, s), 6.60(1H, s), 7.13(1H, d, J=8.4Hz), 7.68(1H, dd, J=8.7, 2.4 Hz), 8.17(1H, d, J=2.4 Hz), 9.72(1H, brs).

-   [2-Acetoxy-5-bromosalicylic acid: It was obtained, using    5-bromosalicylic acid and acetic anhydride as the raw materials, by    the same operation as the Example 34(1) with reference to “European    Journal of Medicinal Chemistry”, (France), 1996, Vol. 31, p.    861-874. It was obtained by the same operation as the following    Example 244(1).]

(3) 5-Bromo-N-{4-[(1,1-dimethyl)ethyl]thiazol-2-yl}-2-hydroxybenzamide(Compound No. 185).

2N Sodium hydroxide (0.2 mL) was added to a solution of2-acetoxy-5-bromo-N-{4-[(1,1-dimethyl)ethyl]thiazol-2-yl}benzamide(100.1 mg, 0.25 mmol) in tetrahydrofuran (3 mL), and the mixture wasstirred at room temperature for 20 minutes. The reaction mixture waspoured into diluted hydrochloric acid and extracted with ethyl acetate.After the ethyl acetate layer was washed with brine, dried overanhydrous sodium sulfate, the residue obtained by evaporation of thesolvent under reduced pressure was crystallized by isopropylether/n-hexane to give the title compound (70.1 mg, 78.9%) as a whitepowder.

¹H-NMR(DMSO-d₆): δ 1.30(9H, s), 6.80(1H, brs), 6.95(1H, brs), 7.57(1H,brs), 8.06(1H, d, J=2.4 Hz), 11.82(1H, brs), 13.27(1H, brs).

Example 186 Preparation of the Compound of Compound No. 186 (1)2-Acetoxy-5-bromo-N-{5-bromo-4-[(1,1-dimethyl)ethyl]thiazol-2-yl}benzamide

N-Bromosuccinimide (97.9 mg, 0.55 mmol) was added to a solution of2-acetoxy-5-bromo-N-{4-[(1,1-dimethyl)ethyl]thiazol-2-yl}benzamide(compound of Example 185(2); 0.20 g, 0.50 mmol) in acetonitrile (10 mL),and the mixture was stirred at room temperature for 1 hour. The residueobtained by evaporation of the solvent under reduced pressure waspurified by column chromatography on silica gel (n-hexane:ethylacetate=3:1) to give the title compound as a crude product.

(2)5-Bromo-N-{5-bromo-4-[(1,1-dimethyl)ethyl]thiazol-2-yl}-2-hydroxybenzamide(Compound No. 186)

Using2-acetoxy-5-bromo-N-{5-bromo-4-[(1,1-dimethyl)ethyl]thiazol-2-yl}-benzamideas the raw material, the same operation as the Example 2 gave the titlecompound.

Yield: 90.9% (2 steps).

¹H-NMR(DMSO-d₆): δ 1.42(9H, s), 6.99(1H, d, J=8.7 Hz), 7.61(1H, dd,J=8.7, 2.7 Hz), 8.02(1H, d, J=2.4 Hz), 11.79(1H, brs), 12.00(1H, brs).

Example 187 Preparation of the Compound of Compound No. 187

Using 5-bromosalicylic acid and2-amino-5-bromo-4-(trifluoromethyl)thiazole as the raw materials, thesame operation as the Example 3 gave the title compound.

Yield: 22.4%.

mp 215° C. (dec.).

¹H-NMR(DMSO-d₆): δ 7.00(1H, d, J=8.8 Hz), 7.61(1H, dd, J=8.8, 2.8 Hz),7.97(1H, d, J=2.4 Hz).

-   [2-Amino-5-bromo-4-(trifluoromethyl)thiazole: Refer to “Journal of    Heterocyclic Chemistry”, (USA), 1991, Vol. 28, p. 1017.]

Example 188 Preparation of the Compound of Compound No. 188 (1) a-Bromo-pivaloylacetonitrile

N-Bromosuccinimide (1.42 g, 7.99 mmol) was added to a solution ofpivaloylacetonitrile (1.00 g, 7.99 mmol) in carbon tetrachloride (15mL), and the mixture was refluxed for 15 minutes. After the reactionmixture was cooled to room temperature, the insoluble matter wasfiltered off, and the residue obtained by evaporation of the filtrateunder reduced pressure was purified by column chromatography on silicagel (n-hexane:ethyl acetate=4:1) to give the title compound (1.43 g,87.9%) as an yellowish brown oil.

¹H-NMR(CDCl₃): δ 1.33(9H, s), 5.10(1H, s).

When the method described in Example 188(1) is referred in the followingexamples, N-bromosuccinimide was used as the brominating agent. As thereaction solvent, solvents such as carbon tetrachloride or the like wereused.

(2) 2-Amino-5-cyano-4-[(1,1-dimethyl)ethyl]thiazole

Using α-bromo-pivaloylacetonitrile and thiourea as the raw materials,the same operation as the Example 185(1) gave the title compound.

Yield: 66.3%.

¹H-NMR(CDCl₃): δ 1.41(9H, s), 5.32(2H, s).

(3)5-Chloro-N-{5-cyano-4-[(1,1-dimethyl)ethyl]thiazol-2-yl}-2-hydroxybenzamide(Compound No. 188)

Using 5-chlorosalicylic acid and2-amino-5-cyano-4-[(1,1-dimethyl)ethyl]thiazole as the raw materials,the same operation as the Example 3 gave the title compound.

Yield: 63.4%.

¹H-NMR(DMSO-d₆): δ 1.43(9H, s), 7.06(1H, d, J=8.7 Hz), 7.51(1H, dd,J=8.7, 3.0 Hz), 7.85(1H, d, J=2.7 Hz), 12.31(2H, br).

Example 189 Preparation of the Compound of Compound No. 189

Using 5-bromosalicylic acid and2-amino-5-cyano-4-[(1,1-dimethyl)ethyl]-thiazole (compound of Example188(2)) as the raw materials, the same operation as the Example 3 gavethe title compound.

Yield: 61.3%.

¹H-NMR(DMSO-d₆): δ 1.43(9H, s), 7.00(1H, d, J=8.7 Hz), 7.62(1H, dd,J=8.7, 2.7 Hz), 7.97(1H, d, J=2.7 Hz), 11.75(1H, br), 12.43(1H, br).

Example 190 Preparation of the Compound of Compound No. 190

Using 5-bromosalicylic acid and 2-amino-5-methylthiazole as the rawmaterials, the same operation as the Example 3 gave the title compound.

Yield: 12.9%.

¹H-NMR(DMSO-d₆): δ 2.33(3H, s), 6.91(1H, d, J=7.6 Hz), 7.26(1H, s),7.54(1H, d, J=9.6 Hz), 8.03(1H, d, J=2.8 Hz).

Example 191 Preparation of the Compound of Compound No. 191

Using 5-bromosalicylic acid and 2-amino-4,5-dimethylthiazole as the rawmaterials, the same operation as the Example 3 gave the title compound.

Yield: 14.4%.

¹H-NMR(DMSO-d₆): δ 2.18(3H, s), 2.22(3H, s), 6.89(1H, d, J=8.8 Hz),7.51(1H, d, J=6.8 Hz), 8.02(1H, d, J=2.8 Hz), 13.23(1H, brs).

Example 192 Preparation of the Compound of Compound No. 192

Using 5-bromosalicylic acid and 2-amino-5-methyl-4-phenylthiazole as theraw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 27.7%.

mp 243-244° C.

¹H-NMR(CD₃OD): δ 2.47(3H, s), 6.92(1H, d, J=8.7 Hz), 7.36-7.41(1H, m),7.44-7.50(2H, m), 7.53(1H, dd, J=9.0, 2.7 Hz), 7.57-7.61(2H, m),8.16(1H, d, J=2.7 Hz).

-   [2-Amino-5-methyl-4-phenylthiazole: Refer to “Yakugaku Zasshi:    Journal of The Pharmaceutical Society of Japan”, 1961, Vol. 81, p.    1456.]

Example 193 Preparation of the Compound of Compound No. 193

Using (4-fluorophenyl)acetone as the raw material, the same operation asthe Examples 188(1)-(3) gave the title compound.

Yield: 28.8% (3 steps).

(1) a -Bromo-(4-fluorophenyl)acetone

¹H-NMR(CDCl₃): δ 2.33(3H, s), 5.41(1H, s), 7.07(2H, t, J=8.7 Hz),7.43(2H, dd, J=8.7, 5.1 Hz).

(2) 2-Amino-4-methyl-5-(4-fluorophenyl)thiazole

¹H-NMR(CDCl₃): δ 2.27(3H, s), 4.88(2H, s), 7.07(2H, t, J=8.7 Hz),7.32(2H, dd, J=8.7, 5.4 Hz).

(3)5-Bromo-N-[4-methyl-5-(4-fluorophenyl)thiazol-2-yl]-2-hydroxybenzamide(Compound No. 193)

¹H-NMR(DMSO-d₆): δ 2.36(3H, s), 6.95(1H, d, J=8.4 Hz), 7.33(2H, t, J=8.7Hz), 7.52-7.59(3H, m), 8.06(1H, d, J=3.0 Hz), 12.01-13.65(2H, br).

Example 194 Preparation of the Compound of Compound No. 194

Using 3-(trifluoromethyl)phenylacetone as the raw material, the sameoperation as the Examples 188(1)-(3) gave the title compound.

Yield: 39.8% (3 steps).

(1) a -Bromo-3-(trifluoromethyl)phenylacetone

¹H-NMR(CDCl₃): δ 2.38(3H, s), 5.43(1H, s), 7.52(1H, t, J=7.8 Hz),7.61-7.66(2H, m), 7.69-7.70(1H, m).

(2) 2-Amino-4-methyl-5-[3-(trifluoromethyl)phenyl]thiazole

¹H-NMR(CDCl₃): δ 2.32(3H, s), 4.95(2H, s), 7.46-7.56(3H, m),7.59-7.61(1H, m).

(3)5-Bromo-N-{4-methyl-5-[3-(trifluoromethyl)phenyl]thiazol-2-yl}-2-hydroxybenzamide(Compound No. 194)

¹H-NMR(DMSO-d₆): δ 2.40(3H, s), 6.97(1H, d, J=8.7 Hz), 7.59(1H, dd,J=8.7, 2.4 Hz), 7.71-7.84(4H, m), 8.06(1H, d, J=2.4 Hz), 12.09(1H, br),12.91-13.63(1H, br).

Example 195 Preparation of the Compound of Compound No. 195

Using 2,2-dimethyl-3-hexanone as the raw material, the same operation asthe Examples 188(1)-(3) gave the title compound.

Yield: 17.0% (3 steps).

(2) 2-Amino-4-[(1,1-dimethyl)ethyl]-5-ethylthiazole

¹H-NMR(CDCl₃): δ 1.21(3H, t, J=7.5 Hz), 1.32(9H, s), 2.79(2H, q, J=7.5Hz), 4.63(2H, brs).

(3)5-Bromo-N-{4-[(1,1-dimethyl)ethyl]-5-ethylthiazol-2-yl}-2-hydroxybenzamide(Compound No. 195)

¹H-NMR(CDCl₃): δ 1.32(3H, t, J=7.5 Hz), 1.41(9H, s), 2.88(2H, q, J=7.5Hz), 6.84(1H, d, J=9.0 Hz), 7.44(1H, dd, J=8.7, 2.4 Hz), 8.05(1H, d,J=2.7 Hz), 11.46(2H, br).

Example 196 Preparation of the Compound of Compound No. 196

Using 5-bromosalicylic acid and 2-amino-4-ethyl-5-phenylthiazole as theraw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 17.4%.

mp 224-225° C.

¹H-NMR(DMSO-d₆): δ 1.24(3H, t, J=7.6 Hz), 2.70(2H, q, J=7.6 Hz),6.95(1H, brd, J=7.6 Hz), 7.39-7.42(1H, m), 7.45-7.51(4H, m), 7.56(1H,brd, J=8.0 Hz), 8.06(1H, d, J=2.8 Hz), 11.98(1H, brs).

Example 197 Preparation of the Compound of Compound No. 197

Using benzyl isopropyl ketone as the raw material, the same operation asthe Examples 188(1)-(3) gave the title compound.

Yield: 4.4% (3 steps).

(2) 2-Amino-4-isopropyl-5-phenylthiazole

¹H-NMR(CDCl₃): δ 1.23(6H, d, J=6.6 Hz), 3.05(1H, m), 4.94(2H, s),7.28-7.41(5H, m).

(3) 5-Bromo-N-(4-isopropyl-5-phenylthiazol-2-yl)-2-hydroxybenzamide(Compound No. 197)

¹H-NMR(DMSO-d₆): δ 1.26(6H, d, J=6.0 Hz), 3.15(1H, m), 6.98(1H, brs),7.43-7.53(5H, m), 7.59(1H, brs), 8.08(1H, d, J=2.7 Hz), 11.90(1H, brd),13.33(1H, brd).

Example 198 Preparation of the Compound of Compound No. 198

Using 1-phenyl-2-hexanone as the raw material, the same operation as theExamples 188(1)-(3) gave the title compound.

Yield: 52.6% (3 steps).

(1) a -Bromo-1-phenyl-2-hexanone

¹H-NMR(CDCl₃): δ 0.85(3H, t, J=7.2 Hz), 1.19-1.32(2H, m), 1, 50-1.60(2H,m), 2.59(2H, td, J=7.5, 3.9 Hz), 5.44(1H, s), 7.34-7.45(5H, m).

(2) 2-Amino-4-butyl-5-phenylthiazole

¹H-NMR(CDCl₃): δ 0.89(3H, t, J=7.5 Hz), 1.28-1.41(2H, m), 1.61-1.71(2H,m), 2.56-2.61(2H, m), 4.87(2H, s), 7.25-7.40(5H, m).

(3) 5-Bromo-N-(4-butyl-5-phenylthiazol-2-yl)-2-hydroxybenzamide(Compound No. 198)

¹H-NMR(DMSO-d₆): δ 0.85(3H, t, J=7.2 Hz), 1.23-1.35(2H, m),1.59-1.69(2H, m), 2.70(2H, t, J=7.2 Hz), 6.96(1H, d, J=6.9 Hz),7.39-7.59(6H, m), 8.07(1H, d, J=2.4 Hz), 11.93(1H, br), 13.18-13.59(1H,br).

Example 199 Preparation of the Compound of Compound No. 199 (1)4-Bromo-2,2,6,6-tetramethyl-3,5-heptanedione [α-Bromo-dipivaloylmethane]

N-Bromosuccinimide (965.8 mg, 5.42 mmol) was added to a solution of2,2,6,6-tetramethyl-3,5-heptanedione (dipivaloylmethane; 1.00 g, 5.42mmol) in carbon tetrachloride (10 mL), and the mixture was refluxed for2 hours. After the reaction mixture was cooled to room temperature, theinsoluble matter was filtered off, and the filtrate was evaporated underreduced pressure to give the title compound (1.42 g, quant.) as a whitecrystal.

¹H-NMR(CDCl₃): δ 1.27(18H, s), 5.67(1H, s).

When the method described in Example 199(1) is referred in the followingexamples, N-bromosuccinimide was used as the brominating agent. As thereaction solvent, solvents such as carbon tetrachloride or the like wereused.

(2) 2-Amino-4-[(1,1-dimethyl)ethyl]-5-[(2,2-dimethyl)propionyl]thiazole

A mixture of 4-bromo-2,2,6,6-tetramethyl-3,5-heptanedione(α-bromo-dipivaloylmethane; 1.42 g, 5.40 mmol), thiourea (451.8 mg, 5.94mmol) and ethanol (15 mL) was refluxed for 2 hours. After the reactionmixture was cooled to room temperature, it was poured into saturatedaqueous sodium hydrogen carbonate and extracted with ethyl acetate.After the ethyl acetate layer was washed successively with water andbrine, dried over anhydrous sodium sulfate, the residue obtained byevaporation of the solvent under reduced pressure was crystallized bydichloromethane/n-hexane to give the title compound (1.23 g, 94.5%) as awhite crystal.

¹H-NMR(CDCl₃): δ 1.26(9H, s), 1.29(9H, s), 5.03(2H, s).

(3)5-Chloro-N-{4-[(1,1-dimethyl)ethyl]-5-[(2,2-dimethyl)propionyl]thiazol-2-yl}-2-hydroxybenzamide(Compound No. 199)

A mixture of 5-chlorosalicylic acid (143.6 mg, 0.83 mmol),2-amino-4-[(1,1-dimethyl)ethyl]ethyl-5-[(2,2-dimethyl)propionyl]thiazole(200.0 mg, 0.83 mmol), phosphorus trichloride (40 μL, 0.46 mmol) andchlorobenzene (4 mL) was refluxed for 3 hours. After the reactionmixture was cooled to room temperature, the residue obtained byconcentration of the solvent under reduced pressure was purified bycolumn chromatography on silica gel (n-hexane:ethyl acetate=3:1) to givethe title compound (159.1 mg, 48.4%) as a white powder.

¹H-NMR(CDCl₃): δ 1.33(9H, s), 1.35(9H, s), 6.99(1H, d, J=8.7 Hz),7.43(1H, dd, J=9.0, 2.7 Hz), 7.70(1H, d, J=2.7 Hz), 10.52(2H, br).

When the method described in Example 199(3) is referred in the followingexamples, phophorus trichloride was used as the acid halogenating agent.As the reaction solvent, solvents such as monochlorobenzene, toluene orthe like were used.

Example 200 Preparation of the Compound of Compound No. 200

Using5-chloro-N-{4-[(1,1-dimethyl)ethyl]-5-[(2,2-dimethyl)propionyl]thiazol-2-yl}-2-hydroxybenzamide(compound No. 199) and acetyl chloride as the raw materials, the sameoperation as the Example 5 gave the title compound.

Yield: 65.3%.

¹H-NMR(CDCl₃): δ 1.32(9H, s), 1.33(9H,s), 2.46(3H, s), 7.22(1H, d, J=8.4Hz), 7.56(1H, dd, J=8.7, 2.4 Hz), 8.05(1H, d, J=2.7 Hz), 9.82(1H, brs).

Example 201 Preparation of the Compound of Compound No. 201

Using 5-bromosalicylic acid and2-amino-4-[(1,1-dimethyl)ethyl]-5-[(2,2-dimethyl)propionyl]thiazole(compound of Example 199(2)) as the raw materials, the same operation asthe Example 199(3) gave the title compound.

Yield: 23.8%.

¹H-NMR(CDCl₃): δ 1.33(9H, s), 1.35(9H, s), 6.94(1H, d, J=8, 7 Hz),7.55(1H, dd, J=8.7, 2.1 Hz), 7.85(1H, d, J=2.1 Hz), 10.51(2H, br).

Example 202 Preparation of the Compound of Compound No. 202

Using pivaloylacetic acid ethyl ester as the raw material, the sameoperation as the Examples 199(1)-(3) gave the title compound.

Yield: 45.7% (3 steps).

(1) a -Bromo-pivaloylacetic acid ethyl ester

¹H-NMR(CDCl₃): δ 1.28(9H, s), 1.29(3H, t, J=7.2 Hz), 4.26(2H, q, J=7.2Hz), 5.24(1H, s).

(2) 2-Amino-4-[(1,1-dimethyl)ethyl]thiazole-5-carboxylic acid ethylester

¹H-NMR(CDCl₃): δ 1.32(3H, t, J=7.2 Hz), 1.43(9H, s), 4.24(2H, q, J=7.2Hz), 5.18(2H, s).

(3)2-(5-Bromo-2-hydroxybenzoyl)amino-4-[(1,1-dimethyl)ethyl]thiazole-5-carboxylicacid ethyl ester (Compound No. 202)

¹H-NMR(DMSO-d₆): δ 1.30(3H, t, J=7.2 Hz), 1.44(9H, s), 4.27(2H, q, J=6.9Hz), 7.00(1H, d, J=8.7 Hz), 7.63(1H, dd, J=8.7, 2.7 Hz), 8.02(1H, d,J=2.4 Hz), 11.80(1H, br), 12.12(1H, br).

Example 203 Preparation of the Compound of Compound No. 203

Using2-(5-bromo-2-hydroxybenzoyl)amino-4-[(1,1-dimethyl)ethyl]thiazole-5-carboxylicacid ethyl ester (Compound No. 202) as the raw material, the sameoperation as the Example 36 gave the title compound.

Yield: 85.5%.

¹H-NMR(DMSO-d₆): δ 1.44(9H, s), 7.00(1H, d, J=9.0 Hz), 7.62(1H, dd,J=9.0, 2.7 Hz), 8.02(1H, d, J=2.4 Hz), 11.83(1H, brs), 12.04(1H, brs),12.98(1H, brs).

Example 204 Preparation of the Compound of Compound No. 204 (1)2-Amino-5-bromo-4-[(1,1-dimethyl)ethyl]thiazole

N-Bromosuccinimide (1.00 g, 5.6 mmol) was added to a solution of2-amino-4-[(1,1-dimethyl)ethyl]thiazole (compound of Example 185(1);0.87 g, 5.6 mmol) in carbon tetrachloride (9 mL), and the mixture wasstirred at room temperature for 1 hour. Hexane was added to the reactionmixture. The insoluble matter was filtered off, and the residue obtainedby evaporation of the filtrate under reduced pressure was purified bycolumn chromatography on silica gel (n-hexane:ethyl acetate=2:1) to givethe title compound 1.23 g, 93.7%) as an yellowish gray powder.

¹H-NMR(CDCl₃): δ 1.39(9H, s), 4.81(2H, brs).

(2) 2-Amino-4-[(1,1-dimethyl)ethyl]-5-piperidinothiazole

A mixture of 2-amino-5-bromo-4-[(1,1-dimethyl)ethyl]thiazole (0.10 g,0.42 mmol), piperidine (0.1 mL), potassium carbonate (0.20 g) andacetonitrile (4 mL) was refluxed for 3 hours. After the reaction mixturewas cooled to room temperature, it was poured into water and extractedwith ethyl acetate. After the ethyl acetate layer was washedsuccessively with water and brine, dried over anhydrous sodium sulfate,the residue obtained by evaporation of the solvent under reducedpressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=2:1) to give the title compound (80.7 mg, 79.3%)as an yellow crystal.

¹H-NMR(CDCl₃): δ 1.32(9H, s), 1.64(4H, t, J=5.7 Hz), 1.71-1.77(2H, m),2.35(2H, brs), 2.99(2H, brs), 4.68(2H, s).

When the preparation method described in Example 204(2) is referred inthe following examples, bases such as potassium carbonate or the likewere used as the base. As the reaction solvent, solvents such asacetonitrile or the like were used.

(3)2-Acetoxy-5-bromo-N-{4-[(1,1-dimethyl)ethyl]-5-piperidinothiazol-2-yl}benzamide

Phosphorus oxychloride (46 μL, 0.50 mmol) was added to a mixture of2-acetoxy-5-bromobenzoic acid (90.3 mg, 0.35 mmol),2-amino-4-[(1,1-dimethyl)ethyl]-5-piperidinothiazole (80.7 mg, 0.34mmol), pyridine (0.1 mL) and tetrahydrofuran (3 mL) under argonatmosphere, and the mixture was stirred at room temperature for 2 hours.The reaction mixture was poured into 2N hydrochloric acid and extractedwith ethyl acetate. After the ethyl acetate layer was washedsuccessively with water and brine, dried over anhydrous sodium sulfate,the residue obtained by evaporation of the solvent under reducedpressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=3:1) to give the title compound (84.3 mg) as acrude product.

When the preparation method described in Example 204(3) is referred inthe following examples, phosphorus oxychloride was used as the acidhalogenating agent. As the reaction base, pyridine was used. As thereaction solvent, solvents such as dichloromethane, tetrahydrofuran orthe like were used.

(4)5-Bromo-N-{4-[(1,1-dimethyl)ethyl]-5-piperidinothiazol-2-yl}-2-hydroxybenzamide(Compound No. 204)

2N Aqueous sodium hydroxide (0.1 mL) was added to a solution of2-acetoxy-5-bromo-N-{4-[(1,1-dimethyl)ethyl]-5-piperidinothiazol-2-yl}benzamide(crude product, 84.3 mg) in ethanol (3 mL), and the mixture was stirredat room temperature for 1 hour. The reaction mixture was poured into 2Nhydrochloric acid and extracted with ethyl acetate. After the ethylacetate layer was washed successively with water and brine, dried overanhydrous sodium sulfate, the residue obtained by evaporation of thesolvent under reduced pressure was purified by column chromatography onsilica gel (n-hexane:ethyl acetate=4:1) to give the title compound (54.1mg, 36.3%; 2 steps) as a white powder.

¹H-NMR(CDCl₃): δ 1.41(9H, s), 1.56(2H, brs), 1.67-1.74(4H, m), 2.79(4H,brs), 6.85(1H, d, J=9.0 Hz), 7.45(1H, dd, J=9.0, 2.4 Hz), 8.06(1H, d,J=2.4 Hz), 11.70(2H, br).

When the preparation method described in Example 204(4) is referred inthe following examples, inorganic bases such as sodium hydroxide,potassium carbonate or the like were used as the base. As the reactionsolvent, solvents such as water, methanol, ethanol, tetrahydrofuran orthe like were used alone or as a mixture.

Example 205 Preparation of the Compound of Compound No. 205

Using 2-amino-5-bromo-4-[(1,1-dimethyl)ethyl]thiazole (compound ofExample 204(1)) and morpholine as the raw materials, the same operationas the Examples 204(2)-(4) gave the title compound.

Yield: 17.1%.

(2) 2-Amino-4-[(1,1-dimethyl)ethyl]-5-morpholinothiazole

¹H-NMR(CDCl₃): δ 1.33(9H, s), 2.76(4H, brs), 3.79(4H, brs), 4.66(2H, s).

(3)2-Acetoxy-5-bromo-N-{4-[(1,1-dimethyl)ethyl]-5-morpholinothiazol-2-yl}benzamide

The product was used for the next reaction as a crude product.

(4)5-Bromo-N-{4-[(1,1-dimethyl)ethyl]-5-morpholinothiazol-2-yl}-2-hydroxybenzamide(Compound No. 205)

¹H-NMR(CDCl₃): δ 1.24(9H, s), 2.89(4H, dd, J=4.8, 4.2 Hz), 3.83(4H, dd,J=4.5, 4.2 Hz), 6.89(1H, d, J=9.0 Hz), 7.49(1H, dd, J=9.0, 2.4 Hz),7.98(1H, d, J=2.1 Hz), 11.20(2H, br).

Example 206 Preparation of the Compound of Compound No. 206

Using 2-amino-5-bromo-4-[(1,1-dimethyl)ethyl]thiazole (compound ofExample 204(1)) and 4-methylpiperazine as the raw materials, the sameoperation as the Examples 204(2)-(4) gave the title compound.

Yield: 6.9%.

(2) 2-Amino-4-[(1,1-dimethyl)ethyl]-5-(4-methylpiperazin-1-yl)thiazole

¹H-NMR(DMSO-d₆): δ 1.25(9H, s), 2.12(2H, brs), 2.19(3H, s), 2.57(2H,brs), 2.72(4H, brs), 6.51(2H, s).

(3)2-Acetoxy-N-{4-[(1,1-dimethyl)ethyl]-5-(4-methylpiperazin-1-yl)thiazol-2-yl}-benzamide

The product was used for the next reaction as a crude product.

(4)5-Bromo-N-{4-[(1,1-dimethyl)ethyl]-5-(4-methylpiperazin-1-yl)thiazol-2-yl}-2-hydroxybenzamide(Compound No. 206)

¹H-NMR(CD₃OD): δ 1.41(9H, s), 2.55(3H, s), 2.87(4H, brs), 3.03(4H, brs),6.88(1H, d, J=8.7 Hz), 7.49(1H, dd, J=8.7, 2.7 Hz), 8.11(1H, d, J=2.7Hz).

Example 207 Preparation of the Compound of Compound No. 207

Using 2-amino-5-bromo-4-[(1,1-dimethyl)ethyl]thiazole (compound ofExample 204(1)) and 4-phenylpiperazine as the raw materials, the sameoperation as the Examples 204(2)-(4) gave the title compound.

Yield: 6.9%.

(2) 2-Amino-4-[(1,1-dimethyl)ethyl]-5-(4-phenylpiperazin-1-yl)thiazole

¹H-NMR(CDCl₃): δ 1.34(9H, s), 2.80(2H, brs), 3.03(4H, brs), 3.55(2H,brs), 4.69(2H, s), 6.88(1H, tt, J=7.2, 1.2 Hz), 6.95(2H, dd, J=9.0, 1.2Hz), 7.28(2H, dd, J=8.7, 7.2 Hz).

(3)2-Acetoxy-5-bromo-N-{4-[(1,1-dimethyl)ethyl]-5-(4-phenylpiperazin-1-yl}thiazol-2-yl]benzamide

The product was used for the next reaction as a crude product.

(4)5-Bromo-N-{4-[(1,1-dimethyl)ethyl]-5-(4-phenylpiperazin-1-yl)thiazol-2-yl}-2-hydroxybenzamide(Compound No. 207)

¹H-NMR(DMSO-d₆): δ 1.39(9H, s), 2.97(4H, s), 3.30(4H, s), 6.82(1H, t,J=7.5 Hz), 6.97(2H, brs), 6.99(2H, t, J=7.5 Hz), 7.58(1H, brs), 8.05(1H,d, J=2.4 Hz), 11.69(1H, brs), 11.82(1H, brs).

Example 208 Preparation of the Compound of Compound No. 208

Using 5-bromosalicylic acid and 2-amino-4-phenylthiazole as the rawmaterials, the same operation as the Example 199(3) gave the titlecompound.

Yield: 16.0%.

mp 239° C. (dec.).

¹H-NMR(DMSO-d₆): δ 7.02(1H, d, J=8.4 Hz), 7.34(1H, t, J=7.6 Hz),7.44(2H, t, J=7.6 Hz), 7.62(1H, dd, J=8.4, 2.8 Hz), 7.67(1H, s),7.92(2H, d, J=7.2 Hz), 8.08(1H, d, J=2.8 Hz), 11.88(1H, brs), 12.05(1H,brs).

Example 209 Preparation of the Compound of Compound No. 209

Using 5-bromosalicylic acid and 2-amino-4-phenylthiazole-5-acetic acidmethyl ester as the raw materials, the same operation as the Example199(3) gave the title compound.

Yield: 32.1%.

mp 288.5-229.5° C.

¹H-NMR(DMSO-d₆): δ 3.66(3H, s), 3.95(2H, s), 6.99(1H, d, J=8.0 Hz),7.42(1H, d, J=6.0 Hz), 7.48(2H, brt, J=7.6 Hz), 7.56-7.61(3H, m),8.07(1H, d, J=2.4 Hz), 11.85(1H, brs), 11.98(1H, brs).

Example 210 Preparation of the Compound of Compound No. 210

2N Sodium hydroxide (0.5 mL, 1 mmol) was added to a solution of{2-[(5-bromo-2-hydroxybenzoyl)amino]-4-phenylthiazol-5-yl}acetic acidmethyl ester (Compound No. 209; 75 mg, 0.17 mmol) in methanol (5 mL),and the mixture was stirred at room temperature for 12 hours. Thereaction mixture was poured into 2N hydrochloric acid and extracted withethyl acetate. After the ethyl acetate layer was washed successivelywith water and brine, dried over anhydrous sodium sulfate, the residueobtained by evaporation of the solvent under reduced pressure was washedwith n-hexane-ethyl acetate under suspension to give the title compound(56 mg, 77.3%) as a light yellow white crystal.

mp 284-286° C.

¹H-NMR(DMSO-d₆): δ 3.84(2H, s), 6.98(1H, d, J=8.8 Hz), 7.42(1H, d, J=6.8Hz), 7.49(2H, t, J=7.6 Hz), 7.58-7.61(3H, m), 8.07(1H, d, J=2.8 Hz),12.25(1H, brs).

Example 211 Preparation of the Compound of Compound No. 211

Using 5-bromosalicylic acid and 2-amino-4,5-diphenylthiazole as the rawmaterials, the same operation as the Example 199(3) gave the titlecompound.

Yield: 25.9%.

mp 262-263° C.

¹H-NMR(DMSO-d₆): δ 7.02(1H, d, J=8.1 Hz), 7.34-7.47(10H, m), 7.63(1H, d,J=6.9 Hz), 8.08(1H, d, J=2.4 Hz), 11.88(1H, brs), 12.08(1H, brs).

-   [2-Amino-4,5-diphenylthiazole: Refer to “Nihon Kagaku Zasshi”, 1962,    Vol. 83, p. 209.]

Example 212 Preparation of the Compound of Compound No. 212

Using 5-bromosalicylic acid and 2-amino-4-benzyl-5-phenylthiazole as theraw materials, the same operation as the Example 199(3) gave the titlecompound.

Yield: 28.1%.

mp 198-200° C.

¹H-NMR(DMSO-d₆): δ 4.08(2H, s), 6.95(1H, d, J=8.8 Hz), 7.15-7.22(3H, m),7.30(2H, t, J=7.6 Hz), 7.38-7.43(1H, m), 7.47(4H, d, J=4.4 Hz), 7.57(1H,brd, J=8.8 Hz), 8.05(1H, d, J=2.4 Hz), 11.98(1H, brs).

-   [2-Amino-4-benzyl-5-phenylthiazole: Refer to “Chemical and    Pharmaceutical Bulletin”, 1962, Vol. 10, p. 376.]

Example 213 Preparation of the Compound of Compound No. 213

Using 5-bromosalicylic acid and2-amino-5-phenyl-4-(trifluoromethyl)thiazole as the raw materials, thesame operation as the Example 199(3) gave the title compound.

Yield: 33.2%.

mp 250° C. (dec.). ¹H-NMR(DMSO-d₆): δ 7.02(1H, d, J=8.8 Hz), 7.51(5H,s), 7.63(1H, dd, J=8.8, 2.4 Hz), 8.02(1H, d, J=2.8 Hz), 12.38(1H, brs).

Example 214 Preparation of the Compound of Compound No. 214

Using 1-phenyl-1,3-butanedione as the raw material, the same operationas the Examples 199(1)-(3) gave the title compound.

Yield: 8.9% (3 steps).

(1) a -Bromo-1-phenyl-1,3-butanedione

¹H-NMR(CDCl₃): δ 2.46(3H, s), 5.62(1H, s), 7.48-7.54(2H, m), 7.64(1H,tt, J=7.5, 2.1 Hz), 7.97-8.01(2H, m).

(2) 2-Amino-5-acetyl-4-phenylthiazole

¹H-NMR(DMSO-d₆): δ 2.18(3H, s), 7.50-7.55(2H, m), 7.59-7.68(3H, m),8.69(2H, brs).

(3) 5-Bromo-N-(5-acetyl-4-phenylthiazol-2-yl)-2-hydroxybenzamide(Compound No. 214)

¹H-NMR(DMSO-d₆): δ 2.44(3H, s), 6.99(1H, d, J=9.0 Hz), 7.55-7.71(4H, m),7.76-7.80(2H, m), 8.01(1H, d, J=2.4 Hz), 12.36(2H, br).

Example 215 Preparation of the Compound of Compound No. 215

Using 1,3-diphenyl-1,3-propanedione as the raw material, the sameoperation as the Examples 199(1)-(3) gave the title compound.

Yield: 49.7%.

(1) a -Bromo-1,3-diphenyl-1,3-propanedione

¹H-NMR(CDCl₃): δ 6.55(1H, s), 7.45-7.50(4H, m), 7.61(2H, tt, J=7.2, 2.1Hz), 7.98-8.01(4H, m).

(2) 2-Amino-5-benzoyl-4-phenylthiazole

¹H-NMR(DMSO-d₆): δ 7.04-7.18(5H, m), 7.22-7.32(3H, m), 7.35-7.38(2H, m),8.02(2H, s).

(3) 5-Bromo-N-(5-benzoyl-4-phenylthiazol-2-yl)-2-hydroxybenzamide(Compound No. 215)

¹H-NMR(DMSO-d₆): δ 7.03(1H, d, J=8.7 Hz), 7.17-7.30(5H, m),7.39-7.47(3H, m), 7.57-7.60(2H, m), 7.64(1H, dd, J=8.7, 2.7 Hz),8.05(1H, d, J=2.4 Hz), 11.82(1H, brs), 12.35(1H, brs).

Example 216 Preparation of the Compound of Compound No. 216

Using 5-bromosalicylic acid and 2-amino-4-phenylthiazole-5-carboxylicacid ethyl ester as the raw materials, the same operation as the Example199(3) gave the title compound.

Yield: 28.6%.

mp 197-199° C.

¹H-NMR(DMSO-d₆): δ 1.21(3H, t, J=6.8 Hz), 4.20(2H, q, J=6.8 Hz),7.01(1H, d, J=8.8 Hz), 7.43-7.48(3H, m), 7.63(1H, dd, J=8.8, 2.4 Hz),7.70-7.72(2H, m), 8.04(1H, d, J=2.4 Hz), 12.33(1H, brs).

Example 217 Preparation of the Compound of Compound No. 217

Using 2-(5-bromo-2-hydroxybenzoyl)amino-4-phenylthiazole-5-carboxylicacid ethyl ester (compound No. 216) as the raw material, the sameoperation as the Example 36 gave the title compound.

Yield: 67.0%.

¹H-NMR(DMSO-d₆): δ 7.00(1H, d, J=8.8 Hz), 7.42-7.44(3H, m), 7.62(1H, dd,J=8.8, 2.4 Hz), 7.70-7.72(2H, m), 8.04(1H, d, J=2.4 Hz), 12.31(1H, brs),12.99(1H, brs).

Example 218 Preparation of the Compound of Compound No. 218

Using 5-chlorosalicylic acid and 2-amino-4-phenylthiazole-5-carboxylicacid ethyl ester as the raw materials, the same operation as the Example199(3) gave the title compound.

Yield: 69.4%.

¹H-NMR(DMSO-d₆): δ 1.22(3H, t, J=7.5 Hz), 4.21(2H, q, J=7.5 Hz),7.07(1H, d, J=8.7 Hz), 7.43-7.47(3H, m), 7.53(1H, dd, J=8.7, 2.4 Hz),7.70-7.74(2H, m), 7.92(1H, d, J=3.0 Hz), 11.88(1H, br), 12.29(1H, brs).

Example 219 Preparation of the Compound of Compound No. 219

Using pentafluorobenzoylacetic acid ethyl ester as the raw material, thesame operation as the Examples 199(1)-(3) gave the title compound.

Yield: 40.0% (3 steps).

(1) a -Bromo-pentafluorobenzoylacetic acid ethyl ester

It was used for the next reaction as a crude product.

(2) 2-Amino-4-(pentafluorophenyl)thiazole-5-carboxylic acid ethyl ester

¹H-NMR(CDCl₃): δ 1.23(3H, t, J=7.2 Hz), 4.21(2H, q, J=7.2 Hz), 5.41(2H,s).

(3) Ethyl2-(5-bromo-2-hydroxybenzoyl)amino-4-(pentafluorophenyl)thiazole-5-carboxylate(Compound No. 219)

¹H-NMR(DMSO-d₆): δ 1.20(3H, t, J=7.2 Hz), 2.51(2H, q, J=7.2 Hz),7.02(1H, d, J=8.7 Hz), 7.64(1H, dd, J=8.7, 2.7 Hz), 7.90(1H, d, J=3.0Hz), 11.92(1H, br), 12.58(1H, br).

Example 220 Preparation of the Compound of Compound No. 220

A mixure of2-(5-bromo-2-hydroxybenzoyl)amino-4-phenylthiazole-5-carboxylic acid(Compound No. 217; 0.20 g, 0.48 mmol), methylamine 40% methanol solution(0.2 ml), 1-hydroxybenzotriazole hydrate (96.7 mg, 0.72 mmol), WSC.HCl(137.2 mg, 0.72 mmol) and tetrahydrofuran (15 mL) was stirred at roomtemperature for 18 hours. The reaction mixture was poured into 2Nhydrochloric acid and extracted with ethyl acetate. After the ethylacetate layer was washed successively with water and brine, dried overanhydrous sodium sulfate, the residue obtained by evaporation of thesolvent under reduced pressure was purified by column chromatography onsilica gel (n-hexane:ethyl acetate=1:2), and crystallized bydichloromethane/n-hexane to give the title compound (87.9 mg, 42.6%) asa white powder.

¹H-NMR(DMSO-d₆): δ 2.70(3H, d, J=4.5 Hz), 7.02(1H, d, J=9.0 Hz),7.40-7.48(3H, m), 7.63(1H, dd, J=9.0, 2.4 Hz), 7.68-7.71(2H, m),8.06(1H, d, J=2.4 Hz), 8.16(1H, t, J=4.5 Hz), 11.88(1H, br), 12.15(1H,brs).

When the method described in Example 220 is referred in the followingexamples, WSC.HCl and 1-hydroxybenzotriazole hydrate were used as thedehydrocondensating agent. As the reaction solvent, solvents such astetrahydrofuran or the like were used.

Example 221 Preparation of the Compound of Compound No. 221

Using 2-(5-bromo-2-hydroxybenzoyl)amino-4-phenylthiazole-5-carboxylicacid (Compound No. 217) and 70% aqueous ethylamine solution as the rawmaterials, the same operation as the Example 220 gave the titlecompound.

Yield: 62.5%.

¹H-NMR(DMSO-d₆): δ 1.05(3H, t, J=6.9 Hz), 3.15-3.24(2H, m), 7.02(1H, d,J=8.7 Hz), 7.40-7.47(3H, m), 7.63(1H, dd, J=8.7, 3.0 Hz), 7.69-7.72(2H,m), 8.06(1H, d, J=2.4 Hz), 8.20(1H, t, J=5.4 Hz), 11.84(1H, br),12.14(1H, brs).

Example 222 Preparation of the Compound of Compound No. 222

Using 2-(5-bromo-2-hydroxybenzoyl)amino-4-phenylthiazole-5-carboxylicacid (Compound No. 217) and isopropylamine as the raw materials, thesame operation as the Example 220 gave the title compound.

Yield: 23.9%.

¹H-NMR(DMSO-d₆): δ 1.07(6H, d, J=6.3 Hz), 4.02(1H, m), 7.02(1H, d, J=9.0Hz), 7.40-7.52(3H, m), 7.64(1H, dd, J=8.7, 2.7 Hz), 7.69-7.73(2H, m),8.06(1H, d, J=2.7 Hz), 11.89(1H, br), 12.14(1H, brs).

Example 223 Preparation of the Compound of Compound No. 223

Using 2-(5-bromo-2-hydroxybenzoyl)amino-4-phenylthiazole-5-carboxylicacid (Compound No. 217) and 2-phenethylamine as the raw materials, thesame operation as the Example 220 gave the title compound.

Yield: 62.2%.

¹H-NMR(DMSO-d₆): δ 2.78(2H, t, J=7.5 Hz), 3.43(2H, q, J=7.5 Hz),7.02(1H, d, J=9.0 Hz), 7.19-7.24(3H, m), 7.27-7.33(2H, m), 7.39-7.41(3H,m), 7.61-7.65(3H, m), 8.06(1H, d, J=2.4 Hz), 8.25(1H, t, J=6.0 Hz),11.85(1H, brs), 12.15(1H, brs).

Example 224 Preparation of the Compound of Compound No. 224

Using 5-bromosalicylic acid and2-amino-4-(trifluoromethyl)thiazole-5-carboxylic acid ethyl ester as theraw materials, the same operation as the Example 199(3) gave the titlecompound.

Yield: 88.7%.

¹H-NMR(DMSO-d₆): δ 1.32(3H, t, J=7.2 Hz), 4.33(2H, q, J=7.2 Hz),7.01(1H, d, J=8.7 Hz), 7.63(1H, dd, J=8.7, 2.7 Hz), 7.98(1H, d, J=2.4Hz), 12.64(1H, br).

Example 225 Preparation of the Compound of Compound No. 225

Using 4-hydroxybiphenyl-3-carboxylic acid and2-amino-4-phenylthiazole-5-carboxylic acid ethyl ester as the rawmaterials, the same operation as the Example 199(3) gave the titlecompound.

Yield: 61.7%.

mp 207-208° C.

¹H-NMR(DMSO-d₆): δ 1.23(3H, t, J=7.2 Hz), 4.22(2H, q, J=7.2 Hz),7.16(1H, d, J=8.7 Hz), 7.36(1H, t, J=7.5 Hz), 7.45-7.50(5H, m),7.69-7.76(4H, m), 7.85(1H, dd, J=8.7, 2.4 Hz), 8.31(1H, d, J=2.4 Hz),11.73(1H, brs), 12.60(1H, brs).

-   [4-Hydroxybiphenyl-3-carboxylic acid: Refer to “Tetrahedron”, (USA),    1997, Vol. 53, p. 11437.]

Example 226 Preparation of the Compound of Compound No. 226

Using (4′-fluoro-4-hydroxybiphenyl)-3-carboxylic acid and2-amino-4-phenylthiazole-5-carboxylic acid ethyl ester as the rawmaterials, the same operation as the Example 199(3) gave the titlecompound.

Yield: 62.7%.

mp 237-238° C.

¹H-NMR(DMSO-d₆): δ 1.22(3H, t, J=7.2 Hz), 4.21(2H, q, J=7.2 Hz),7.13(1H, d, J=8.4 Hz), 7.28(2H, t, J=8.8 Hz), 7.44-7.45(3H, m),7.71-7.75(4H, m), 7.81(1H, dd, J=8.8, 2.4 Hz), 8.27(1H, d, J=2.4 Hz),11.67(1H, brs), 12.58(1H, brs).

-   [(4′-Fluoro-4-hydroxybiphenyl)-3-carboxylic acid: Refer to    “Tetrahedron”, 1997, Vol. 53, p. 11437.]

Example 227 Preparation of the Compound of Compound No. 227

Using (2′,4′-difluoro-4-hydroxybiphenyl)-3-carboxylic acid and2-amino-4-phenylthiazole-5-carboxylic acid ethyl ester as the rawmaterials, the same operation as the Example 199(3) gave the titlecompound.

Yield: 45.6%.

mp 206-207° C.

¹H-NMR(DMSO-d₆): δ 1.22(3H, t, J=7.2 Hz), 4.22(2H, q, J=7, 2 Hz),7.17(1H, d, J=9.0 Hz), 7.21(1H, td, J=8.7, 2.4 Hz), 7.38(1H, ddd,J=11.7, 9.3, 2.4 Hz), 7.44-7.46(3H, m), 7.60-7.75(4H, m), 8.13-8.14(1H,m), 11.86(1H, brs), 12.46(1H, brs).

Example 228 Preparation of the Compound of Compound No. 228 (1)[4-Hydroxy-4′-(trifluoromethyl)biphenyl]-3-carboxylic acid

A mixture of 5-bromosalicylic acid (500 mg, 2.30 mmol),dihydroxy-4-(trifluoromethyl)phenylborane (488 mg, 2.57 mmol), palladiumacetate (10 mg, 0.040 mmol) and 1 mol/L aqueous sodium carbonate (7 mL)was stirred at 80° C. for 1 hour. After the reaction mixture was cooledto room temperature, it was poured into 2N hydrochloric acid andextracted with ethyl acetate. After the ethyl acetate layer was washedsuccessively with water and brine, dried over anhydrous sodium sulfate,the residue obtained by evaporation of the solvent under reducedpressure was methyl-esterified by trimethylsilyldiazomethane andmethanol according to the fixed procedure, and purified by columnchromatography on silica gel (n-hexane:ethyl acetate=5:1) to give acolourless liquid (563 mg). 2N Sodium hydroxide (3 mL) was added to asolution of this liquid in methanol (10 mL), and the mixture was stirredat 60° C. for 1 hour. After the reaction mixture was cooled to roomtemperature, it was poured into 2N hydrochloric acid and extracted withethyl acetate. After the ethyl acetate layer was washed successivelywith water and brine, dried over anhydrous magnesium sulfate, theresidue obtained by evaporation of the solvent under reduced pressurewas washed with n-hexane/dichloromethane under suspension to give thetitle compound (458 mg, 70.4%) as a white crystal.

mp 185° C. (dec.).

¹H-NMR(DMSO-d₆): δ 7.09(1H, d, J=8.8 Hz), 7.77(2H, d, J=8.0 Hz),7.85(2H, d, J=8.0 Hz), 7.90(1H, dd, J=8.8, 2.0 Hz), 8.10(1H, d, J=2.4Hz), 11.80(1H, brs).

(2)2-{[4-Hydroxy-4′-(trifluoromethyl)biphenyl]-3-carbonyl}amino-4-phenylthiazole-5-carboxylicacid ethyl ester (Compound No. 228)

Using [4-hydroxy-4′-(trifluoromethyl)biphenyl]-3-carboxylic acid and2-amino-4-phenylthiazole-5-carboxylic acid ethyl ester as the rawmaterials, the same operation as the Example 199(3) gave the titlecompound.

Yield: 41.7%.

mp 236-237° C.

¹H-NMR(DMSO-d₆): δ 1.22(3H, t, J=7.2 Hz), 4.21(2H, q, J=7.2 Hz),7.18(1H, d, J=8.8 Hz), 7.44-7.45(3H, m), 7.72-7.74(2H, m), 7.81(2H, d,J=8.4 Hz), 7.91(1H, dd, J=8.8, 2.4 Hz), 7.93(2H, d, J=8.4 Hz), 8.36(1H,d, J=2.4 Hz), 11.78(1H, brs), 12.62(1H, brs).

Example 229 Preparation of the Compound of Compound No. 229

Using 2-hydroxy-5-(1-pyrrolyl)benzoic acid and2-amino-4-phenylthiazole-5-carboxylic acid ethyl ester as the rawmaterials, the same operation as the Example 199(3) gave the titlecompound.

Yield: 55.0%.

¹H-NMR(DMSO-d₆): δ 1.22(3H, t, J=7.2 Hz), 4.22(2H, q, J=7.2 Hz),6.26(2H, t, J=2.1 Hz), 7.13(1H, d, J=8.7 Hz), 7.32(2H, t, J=2.1 Hz),7.43-7.47(3H, m), 7.70-7.75(3H, m), 8.09(1H, d, J=2.7 Hz), 11.58(1H,brs), 12.55(1H, brs).

Example 230 Preparation of the Compound of Compound No. 230 (1)2-Hydroxy-5-(2-thienyl)benzoic acid

Tetrakis(triphenylphosphine)palladium (80 mg, 0.07 mmol) was added to asolution of 5-bromosalicylic acid (500 mg, 2.30 mmol) in1,2-dimethoxyethane (5 mL) under argon atmosphere, and the mixture wasstirred at room temperature for 10 minutes. Thendihydroxy-2-thienylborane (324 mg, 2.53 mmol) and 1M sodium carbonate (7mL) were added to the mixture, and it was refluxed for 2 hours. Afterthe reaction mixture was cooled to room temperature, it was poured into2N hydrochloric acid and extracted with ethyl acetate. After the ethylacetate layer was washed successively with water and brine, dried overanhydrous sodium sulfate, the residue obtained by evaporation of thesolvent under reduced pressure was methyl-esterified bytrimethylsilyldiazomethane and methanol according to the fixedprocedure, and purified by column chromatography on silica gel(n-hexane:ethyl acetate=5:1) to give an yellow liquid (277 mg). 2NSodium hydroxide (1.5 mL) was added to a solution of this liquid inmethanol (5 mL), and the mixture was stirred at 60° C. for 1 hour. Afterthe reaction mixture was cooled to room temperature, it was poured into2N hydrochloric acid and extracted with ethyl acetate. After the ethylacetate layer was washed successively with water and brine, dried overanhydrous magnesium sulfate, the residue obtained by evaporation of thesolvent under reduced pressure was crystallized fromn-hexane/dichloromethane to give the title compound (58 mg, 11.5%) as awhite crystal.

¹H-NMR(DMSO-d₆): δ 6.95(1H, d, J=8.8 Hz), 7.09(1H, dd, J=4.8, 3.6 Hz),7.37(1H, dd, J=4.0, 1.2 Hz), 7.45(1H, dd, J=5.2, 1.2 Hz), 7.74(1H, dd,J=8.8, 2.8 Hz), 7.96(1H, d, J=2.8 Hz).

(2)2-[2-Hydroxy-5-(2-thienyl)benzoyl]amino-4-phenylthiazole-5-carboxylicacid ethyl ester (Compound No. 230)

Using 2-hydroxy-5-(2-thienyl)benzoic acid and2-amino-4-phenylthiazole-5-carboxylic acid ethyl ester as the rawmaterials, the same operation as the Example 199(3) gave the titlecompound.

Yield: 58.2%.

mp 213-214° C.

¹H-NMR(DMSO-d₆): δ 1.22(3H, t, J=7.2 Hz9, 4.21(2H, q, J=7.2 Hz),7.10(1H, d, J=9.2 Hz), 7.12(1H, dd, J=4.8, 3.6 Hz), 7.44-7.46(4H, m),7.50(1H, dd, J=4.8, 1.2 Hz), 7.71-7.74(2H, m), 7.79(1H, dd, J=8.8, 2.4Hz), 8.21(1H, d, J=2.4 Hz), 11.78(1H, brs), 12.44(1H, brs).

Example 231 Preparation of the Compound of Compound No. 231 (1)2-Amino-4-[3,5-bis(trifluoromethyl)phenyl]thiazole

Phenyltrimethylammonium tribromide (753 mg, 2 mmol) was added to asolution of 3′,5′-bis(trifluoromethyl)acetophenone (0.51 g, 2.0 mmol) intetrahydrofuran (5 mL) and the mixture was stirred at room temperaturefor 5 hours. The reaction mixture was poured into water and extractedwith ethyl acetate. After the ethyl acetate layer was washed with brine,dried over anhydrous sodium sulfate, ethanol (5 mL) and thiourea (152mg, 2 mmol) were added to the residue obtained by evaporation of thesolvent under reduced pressure, and the mixture was refluxed for 30minutes. After the reaction mixture was cooled to room temperature, itwas poured into saturated aqueous sodium hydrogen carbonate andextracted with ethyl acetate. After the ethyl acetate layer was washedwith brine and dried over anhydrous sodium sulfate, the residue obtainedby evaporation of the solvent under reduced pressure was purified bycolumn chromatography on silica gel (n-hexane:ethyl acetate=2:1) andwashed with n-hexane under suspension to give the title compound (520.1mg, 83.3%) as a light yellow white crystal.

¹H-NMR(CDCl₃): δ 5.03(2H, s), 6.93(1H, s), 7.77(1H, s), 8.23(2H, s).

(2)5-Chloro-2-hydroxy-N-{4-[3,5-bis(trifluoromethyl)phenyl]thiazol-2-yl}benzamide(Compound No. 231)

A mixture of 5-chlorosalicylic acid (172.6 mg, 1 mmol),2-amino-4-[3,5-bis(trifluoromethyl)phenyl]thiazole (312.2 mg, 1 mmol),phosphorus trichloride (44 μL, 0.5 mmol) and monochlorobenzene (5 mL)was refluxed for 4 hours. After the reaction mixture was cooled to roomtemperature, it was poured into water and extracted with ethyl acetate.After the ethyl acetate layer was washed with brine, dried overanhydrous sodium sulfate, the residue obtained by evaporation of thesolvent under reduced pressure was purified by column chromatography onsilica gel (n-hexane:ethyl acetate=3:1→2:1) to give the title compound(109.8 mg, 23.5%) as a pale yellow white powder.

¹H-NMR(DMSO-d₆): δ 7.08(1H, d, J=8.7 Hz), 7.53(1H, dd, J=9.0, 3.0 Hz),7.94(1H, d, J=3.0 Hz), 8.07(1H, s), 8.29(1H, s), 8.60(2H, s), 11.77(1H,s), 12.23(1H, s).

Example 232 Preparation of the Compound of Compound No. 232

Using 5-chlorosalicylic acid and2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid ethylester as the raw materials, the same operation as the Example 3 gave thetitle compound.

Yield: 49.6%.

¹H-NMR(DMSO-d₆): δ 1.32(3H, t, J=7.2 Hz), 1.74(4H, br), 2.63(2H, br),2.75(2H, br), 4.30(2H, q, J=7.2 Hz), 7.05(1H, d, J=9.0 Hz), 7.50(1H, dd,J=8.7, 3.0 Hz), 7.92(1H, d, J=3.0 Hz), 12.23(1H, s), 13.07(1H, s).

Example 233 Preparation of the Compound of Compound No. 233

Using 5-bromosalicylic acid and 3-amino-5-phenylpyrazole as the rawmaterials, the same operation as the Example 3 gave the title compound.

Yield: 9.2%.

¹H-NMR(DMSO-d₆): δ 6.98(1H, d, J=8.8 Hz), 7.01(1H, s), 7.35(1H, t, J=7.6Hz), 7.46(2H, t, J=7.6 Hz), 7.58(1H, dd, J=8.8, 2.8 Hz), 7.74-7.76(2H,m), 8.19(1H, s), 10.86(1H, s), 12.09(1H, s), 13.00(1H, brs).

Example 234 Preparation of the Compound of Compound No. 234 (1)2-Amino-4,5-diethyloxazole

Cyanamide (0.75 g, 17.7 mmol) and sodium ethoxide 1.21 g, 17.7 mmol)were added to a solution of propioin (1.03 g, 8.87 mmol) in ethanol (15mL), and the mixture was stirred at room temperature for 3.5 hours. Thereaction mixture was poured into water and extracted with ethyl acetate.After the ethyl acetate layer was washed successively with water andbrine, dried over anhydrous sodium sulfate, the residue obtained byevaporation of the solvent under reduced pressure was purified by columnchromatography on silica gel (dichloromethane:methanol=9:1) to give thetitle compound (369.2 mg, 29.7%) as an yellow amorphous.

¹H-NMR(DMSO-d₆): δ 1.04(3H, t, J=7.5 Hz), 1.06(3H, t, J=7.5 Hz),2.20(2H, q, J=7.5 Hz), 2.43(2H, q, J=7.5 Hz), 6.15(2H, s).

(2) 2-Acetoxy-5-bromo-N-(4,5-diethyloxazol-2-yl)benzamide

Using 2-acetoxy-5-bromobenzoic acid and 2-amino-4,5-diethyloxazole asthe raw materials, the same operation as the Example 5 gave the titlecompound.

Yield: 22.0%.

¹H-NMR(CDCl₃): δ 1.22(3H, t, J=7.5 Hz), 1.23(3H, t, J=7.5 Hz), 2.38(3H,s), 2.48(2H, q, J=7.5 Hz), 2.57(2H, q, J=7.5 Hz), 6.96(1H, d, J=8.7 Hz),7.58(1H, dd, J=8.7, 2.7 Hz), 8.32(1H, s), 11.40(1H, br).

(3) 5-Bromo-N-(4,5-diethyloxazol-2-yl)-2-hydroxybenzamide (Compound No.234)

Using 2-acetoxy-5-bromo-N-(4,5-diethyloxazol-2-yl)benzamide as the rawmaterial, the same operation as the Example 2 gave the title compound.

Yield: 70.2%.

¹H-NMR(CDCl₃) δ :1.25(3H, t, J=7.5 Hz), 1.26(3H, t, J=7.5 Hz), 2.52(2H,q, J=7.5 Hz), 2.60(2H, q, J=7.5 Hz), 6.84(1H, d, J=8.7 Hz), 7.43(1H, dd,J=8.7, 3.0 Hz), 8.17(1H, d, J=3.0 Hz), 11.35(1H, br), 12.83(1H, br).

Example 235 Preparation of the Compound of Compound No. 235

Using 5-bromosalicylic acid and 2-amino-4,5-diphenyloxazole as the rawmaterials, the same operation as the Example 3 gave the title compound.

Yield: 32.6%.

mp 188-189° C.

¹H-NMR(DMSO-d₆): δ 6.98(1H, d, J=8.7 Hz), 7.40-7.49(6H, m),7.53-7.56(2H, m), 7.59-7.63(3H, m), 8.01(1H, d, J=2.4 Hz), 11.80(2H,brs).

-   [2-Amino-4,5-diphenyloxazole: Refer to “Zhournal Organicheskoi    Khimii: Russian Journal of Organic Chemistry”, (Russia), 1980, Vol.    16, p. 2185.]

Example 236 Preparation of the Compound of Compound No. 236 (1)2-Amino-4,5-bis(furan-2-yl)oxazole

Cyanamide (218.8 mg, 5.20 mmol) and sodium ethoxide (530.8 mg, 7.80mmol) were added to a solution of furoin (0.50 g, 2.60 mmol) in ethanol(15 mL), and the mixture was stirred at room temperature for 2 hours.The reaction mixture was poured into water and extracted with ethylacetate. After the ethyl acetate layer was washed successively withwater and brine, dried over anhydrous sodium sulfate, the residueobtained by evaporation of the solvent under reduced pressure waspurified by column chromatography on silica gel (n-hexane:ethylacetate=1:1→1:2) to give the title compound (175.0 mg, 31.1%) as a darkbrown crystal.

¹H-NMR(DMSO-d₆): δ 6.59(1H, dd, J=3.3, 2.1 Hz), 6.62(1H, dd, J=3.3, 2.1Hz), 6.73(1H, dd, J=3.3, 0.6 Hz), 6.80(1H, dd, J=3.3, 0.9 Hz), 7.05(2H,s), 7.75-7.76(2H, m).

(2) 5-Bromo-N-[4,5-bis(furan-2-yl)oxazol-2-yl]-2-hydroxybenzamide(Compound No. 236)

Using 5-bromosalicylic acid and 2-amino-4,5-bis(furan-2-yl)oxazole asthe raw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 12.9%.

¹H-NMR(DMSO-d₆): δ 6.65(1H, dd, J=3.6, 1.8 Hz), 6.68(1H, dd, J=3.6, 1.8Hz), 6.75(1H, d, J=8, 7 Hz), 6.92(1H, dd, J=3.6, 0.9 Hz), 6.93(1H, d,J=3.3 Hz), 7.37(1H, dd, J=8.7, 2.7 Hz), 7.80(1H, dd, J=1.8, 0.9 Hz),7.84(1H, dd, J=1.8, 0.9 Hz), 7.92(1H, d, J=3.0 Hz), 14.88(2H, br).

Example 237 Preparation of the Compound of Compound No. 237 (1)2-Acetoxy-N-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)benzamide

Using O-acetylsalicyloyl chloride and2-amino-5-trifluoromethyl-1,3,4-thiadiazole as the raw materials, thesame operation as the Example 1 gave the title compound.

Yield: 51.1%.

¹H-NMR(DMSO-d₆): δ 2.23(3H, s), 7.32(1H, dd, J=8.0, 1.2 Hz), 7.45(1H,td, J=7.6, 1.2 Hz), 7.69(1H, td, J=8.0, 2.0 Hz), 7.87(1H, dd, J=8.0, 2.0Hz), 13.75(1H, brs).

(2) 2-Hydroxy-N-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)benzamide(Compound No. 237)

Using 2-acetoxy-N-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)benzamide asthe raw material, the same operation as the Example 2 gave the titlecompound.

Yield: 92.9%.

¹H-NMR(DMSO-d₆): δ 7.00(1H, td, J=8.0, 0.8 Hz), 7.06(1H, d, J=8.4 Hz),7.51(1H, ddd, J=8.4, 7.6, 2.0 Hz), 7.92(1H, dd, J=8.0, 1.6 Hz),12.16(1H, br).

Example 238 Preparation of the Compound of Compound No. 238

Using 5-bromosalicylic acid and2-amino-5-trifluoromethyl-1,3,4-thiadiazole as the raw materials, thesame operation as the Example 3 gave the title compound.

Yield: 80.2%.

¹H-NMR(DMSO-d₆): δ 7.01(1H, d, J=9.0 Hz), 7.63(1H, dd, J=8.7, 2.7 Hz),7.97(1H, d, J=2.4 Hz).

Example 239 Preparation of the Compound of Compound No. 239

Using 5-chlorosalicylic acid and 3-aminopyridine as the raw materials,the same operation as the Example 3 gave the title compound.

Yield: 23.2%.

¹H-NMR(DMSO-d₆): δ 7.02(1H, d, J=9.3 Hz), 7.42(1H, ddd, J=9.0, 4.8, 0.6Hz), 7.47(1H, dd, J=8.7, 5.7 Hz), 7.92(1H, d, J=2.7 Hz), 8.15(1H, ddd,J=8.4, 2.4, 1.5 Hz), 8.35(1H, dd, J=7.8, 1.5 Hz), 8.86(1H, d, J=2.4 Hz),10.70(1H, s).

Example 240 Preparation of the Compound of Compound No 240

Using 5-chlorosalicylic acid and 5-amino-2-chloropyridine as the rawmaterials, the same operation as the Example 3 gave the title compound.

Yield: 12.2%.

¹H-NMR(DMSO-d₆): δ 7.04(1H, d, J=9.0 Hz), 7.49(1H, dd, J=9.0, 3.0 Hz),7.54(1H, d, J=8.4 Hz), 7.88(1H, d, J=2.7 Hz), 8.21(1H, dd, J=8.7, 2.7Hz), 8.74(1H, d, J=2.7 Hz), 10.62(1H, s), 11.57(1H, s).

Example 241 Preparation of the Compound of Compound No. 241

Using 5-chlorosalicylic acid and 2-amino-6-chloro-4-methoxypyrimidine asthe raw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 2.2%, white solid.

¹H-NMR(DMSO-d₆): δ 3.86(3H, s), 6.85(1H, s), 7.01(1H, d, J=9.0 Hz),7.47(1H, dd, J=9.0, 3.0 Hz), 7.81(1H, d, J=3.0 Hz), 11.08(1H, s),11.65(1H, s).

Example 242 Preparation of the Compound of Compound No. 242

Using 5-chlorosalicylic acid and 3-aminoquinoline as the raw materials,the same operation as the Example 3 gave the title compound.

Yield: 4.3%.

¹H-NMR(DMSO-d₆): δ 7.07(1H, d, J=8.7 Hz), 7.51(1H, dd, J=9.0, 3.0 Hz),7.61(1H, dt, J=7.8, 1.2 Hz), 7.70(1H, dt, J=7.8, 1.5 Hz), 7.98(2H, d,J=3.0 Hz), 8.01(1H, s), 8.82(1H, d, J=2.4 Hz), 10.80(1H, s), 11.74(1H,s).

Example 243 Preparation of the Compound of Compound No. 243

Using 5-chlorosalicylic acid and 2-amino-6-bromopyridine as the rawmaterials, the same operation as the Example 3 gave the title compound.

Yield: 12.3%.

¹H-NMR(DMSO-d₆): δ 7.07(1H, d, J=8.7 Hz), 7.42(1H, d, J=7.8 Hz),7.51(1H, dd, J=8.7, 2.7 Hz), 7.82(1H, t, J=7.5 Hz), 7.94(1H, d, J=3.0Hz), 8.24(1H, d, J=7.8 Hz), 10.95(1H, s), 11.97(1H, s).

Example 244 Preparation of the Compound of Compound No. 244 (1)2-Acetoxy-5-chlorobenzoic acid

Concentrated sulfuric acid (0.08 mL) was added slowly to a mixture of5-chlorosalicylic acid (13.35 g, 77 mmol) and acetic anhydride (20 mL).After the reaction mixture was solidified, it was poured into ice waterand extracted with ethyl acetate. The organic layer was washed withwater and brine, and dried over anhydrous sodium sulfate. The residueobtained by evaporation of the solvent under reduced pressure was washedwith n-hexane under suspension to give the title compound (15.44 g,93.0%) as a white crystal.

¹H-NMR(DMSO-d₆): δ 2.25(3H, s), 7.27(1H, d, J=8.7 Hz), 7.72(1H, dd,J=8.7, 2.7 Hz), 7.89(1H, d, J=2.7 Hz), 13.47(1H, s).

(2) 2-Acetoxy-5-chloro-N-(pyridazin-2-yl)benzamide

Using 2-acetoxy-5-chlorobenzoic acid and 2-aminopyridazine as the rawmaterials, the same operation as the Example 204(3) gave the titlecompound.

Yield: 19.7%.

¹H-NMR(CDCl₃): δ 2.42(3H, s), 7.19(1H, d, J=8.7 Hz), 7.54(1H, dd, J=8.7,2.7 Hz), 8.01(1H, d, J=2.4 Hz), 8.28(1H, dd, J=2.4, 1.8 Hz), 8.42(1H, d,J=2.4 Hz), 9.09(1H, s), 9.66(1H, d, J=1.8 Hz).

(3) 5-Chloro-2-hydroxy-N-(pyridazin-2-yl)benzamide (Compound No. 244)

Using 2-acetoxy-5-chloro-N-(pyridazin-2-yl)benzamide as the rawmaterial, the same operation as the Example 2 gave the title compound.

Yield: 72.6%.

¹H-NMR(DMSO-d₆): δ 7.09(1H, d, J=9.0 Hz), 7.52(1H, dd, J=8.7, 2.7 Hz),7.96(1H, d, J=2.7 Hz), 8.44-8.47(2H, m), 9.49(1H, s), 10.99(1H, s),12.04(1H, s).

Example 245 Preparation of the Compound of Compound No. 245

Using 5-bromosalicylic acid and 2-amino-5-bromopyrimidine as the rawmaterials, the same operation as the Example 3 gave the title compound.

Yield: 10.3%.

¹H-NMR(DMSO-d₆): δ 6.98(1H, d, J=8.8 Hz), 7.59(1H, dd, J=8.8, 2.4 Hz),8.00(1H, d, J=2.8 Hz), 8.86(2H, s), 11.09(1H, s), 11.79(1H, s).

Example 246 Preparation of the Compound of Compound No. 246

Using 2-(5-bromo-2-hydroxybenzoyl)amino-4-phenylthiazole-5-carboxylicacid (Compound No. 217) and propylamine as the raw materials, the sameoperation as the Example 220 gave the title compound.

Yield: 23.1%.

¹H-NMR(DMSO-d₆): δ 0.82(3H, t, J=7.5 Hz), 1.39-1.51(2H, m), 3.13(2H, q,J=6.6 Hz), 7.02(1H, d, J=9.0 Hz), 7.40-7.48(3H, m), 7.63(1H, dd, J=8.7,2.7 Hz), 7.68-7.72(2H, m), 8.06(1H, d, J=2.7 Hz), 8.18(1H, t, J=5.7 Hz),11.87(1H, brs), 12.14(1H, brs).

Example 247 Preparation of the Compound of Compound No. 247

A mixture of 5-sulfosalicylic acid (218 mg, 1 mmol),3,5-bis(trifluoromethyl)aniline (229 mg, 1 mmol), phosphorus trichloride(88,” L, 1 mmol) and o-xylene (5 mL) was refluxed for 3 hours. After thereaction mixture was cooled to room temperature, it was purified bycolumn chromatography on silica gel (n-hexane:ethyl acetate=3:1) to givethe title compound (29 mg, 9.2%) as a white solid.

¹H-NMR(DMSO-d₆): δ 7.15(1H, d, J=8.8 Hz), 7.65(2H, s), 7.73(1H, s),7.81(1H, s), 7.82(1H, dd, J=8.7, 2.5 Hz), 8.23(1H, d, J=2.5 Hz),8.38(2H, s), 10.87(1H, s), 11.15(1H, brs).

Example 248 Preparation of the Compound of Compound No. 248

A mixture of 5-chlorosalicylic acid (87 mg, 0.5 mmol),2,2-bis(3-amino-4-methylphenyl)-1,1,1,3,3,3-hexafluoropropane (363 mg, 1mmol), phosphorus trichloride (44 μL, 0.5 mmol) and toluene (4 mL) wasrefluxed for 4 hours. After the reaction mixture was cooled to roomtemperature, it was purified by column chromatography on silica gel(n-hexane:ethyl acetate=5:1) to give the white title compound (16 mg,4.9%). (The compound of Compound No. 251 described in the followingExample 251 was obtained as a by-product.)

¹H-NMR(DMSO-d₆): δ 2.34(6H, s), 7.04(4H, d, J=8.8 Hz), 7.39(2H, d, J=8.4Hz), 7.48(2H, dd, J=8.8, 2.9 Hz), 7.96(2H, d, J=2.9 Hz), 8.19(2H, s),10.44(2H, s), 12.17(2H, s).

Example 249 Preparation of the Compound of Compound No. 249

Using 3-phenylsalicylic acid and 3,5-bis(trifluoromethyl)aniline as theraw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 64.6%.

¹H-NMR(DMSO-d₆): δ 7.12(1H, t, J=8.1 Hz), 7.37(1H, tt, J=7.5, 1.5 Hz),7.43-7.48(2H, m), 7.56-7.60(3H, m), 7.91(1H, s), 8.07, (1H, dd, J=8.1,1.5 Hz), 8.48(2H, s), 11.00(1H, s), 12.16(1H, s).

Example 250 Preparation of the Compound of Compound No. 250

Using 4-fluorosalicylic acid and 3,5-bis(trifluoromethyl)aniline as theraw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 65.7%.

¹H-NMR(DMSO-d₆): δ 6.81-6.90(2H, m), 7.84(1H, s,), 7.93-7.98(1H, m,),8.45(2H, s,), 10.78(1H, s), 11.81(1H, s,).

Example 251 Preparation of the Compound of Compound No. 251

This compound was obtained by separation from the mixture with thecompound of Compound No. 248 described in the aforementioned Example248.

Yield: 9.4%.

¹H-NMR(CD₃OD): δ 2.16(3H, s), 2.34(3H, s), 6.69(1H, d, J=8.2 Hz),6.76(1H, brs) 6.95(1H, d, J=8.8 Hz), 7.02(1H, d, J=8.0 Hz), 7.15(1H, d,J=8.2 Hz), 7.29(1H, d, J=8.2 Hz), 7.37(1H, dd, J=8.8, 2.6 Hz), 7.97(1H,d, J=2.6 Hz), 7.98(1H, s).

Example 252 Preparation of the Compound of Compound No. 252

Using 5-chlorosalicylic acid and4-[2-amino-4-(trifluromethyl)phenoxy]-benzonitrile as the raw materials,the same operation as the Example 3 gave the title compound.

Yield: 11.6%.

¹H-NMR(CD₃OD): δ 6.88(1H, d, J=8.6 Hz), 7.19(2H, d, J=8.9 Hz), 7.24(1H,d, J=8.6 Hz), 7.33(1H, dd, J=8.8, 2.8 Hz), 7.46(1H, dd, J=8.9, 1.9 Hz),7.76(2H, d, J=8.9 Hz), 7.98(1H, d, J=2.7 Hz), 8.96(1H, s).

Example 253 Preparation of the Compound of Compound No. 253

Using 5-chlorosalicylic acid and3-amino-4-(4-methoxyphenoxy)benzotrifluoride as the raw materials, thesame operation as the Example 3 gave the title compound.

Yield: 88.1%.

¹H-NMR(CDCl₃): δ 3.85(3H, s) 6.81(1H, d, J=8.5 Hz), 6.97-7.02(3H, m),7.08(2H, d, J=8.8 Hz), 7.30(1H, m), 7.40(1H, dd, J=8.8, 1.9 Hz),7.45(1H, d, J=2.2 Hz), 8.70(1H, s), 8.78(1H, d, J=1.6 Hz), 11.76(1H, s).

Example 254 Preparation of the Compound of Compound No. 254

Using salicylic acid and 2,5-bis(trifluoromethyl)aniline as the rawmaterials, the same operation as the Example 3 gave the title compound.

Yield: 47.8%.

¹H-NMR(CD₃OD): δ 7.00-7.06(2H, m), 7.48(1H, dt, J=1.5, 7.5 Hz), 7.74(1H,d, J=8.4 Hz), 8.01-8.08(2H, m), 8.79(1H, s), 11.09(1H, s), 12.03(1H, s).

Example 255 Preparation of the Compound of Compound No. 255 (1)2-Amino-4-(2,4-dichlorophenyl)thiazole

Using 2′,4′-dichloroacetophenone and thiourea as the raw materials, thesame operation as the Example 231(1) gave the title compound.

Yield: 97.1%.

¹H-NMR(CDCl₃): δ 5.01(2H, s), 7.09(1H, s), 7.28(1H, dd, J=8.4, 2.1 Hz),7.45(1H, d, J=2.1 Hz), 7.82(1H, d, J=8.4 Hz).

(2) 5-Chloro-2-hydroxy-N-[4-(2,4-dichlorophenyl)thiazol-2-yl]benzamide(Compound No. 255)

Using 5-chlorosalicylic acid and 2-amino-4-(2,4-dichlorophenyl)thiazoleas the raw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 8.0%.

¹H-NMR(DMSO-d₆): δ 7.08(1H, d, J=8.7 Hz), 7.50-7.55(2H, m),7.72-7.76(2H, m), 7.91(1H, d, J=8.4 Hz), 7.95(1H, d, J=2.4 Hz),11.87(1H, brs), 12.09(1H, brs).

Example 256 Preparation of the Compound of Compound No. 256

Using 3-isopropylsalicylic acid and 3,5-bis(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 99.2%.

¹H-NMR(CDCl₃): δ 1.26(6H, d, J=6.9 Hz), 3.44(1H, Hept, J=6.9 Hz),6.92(1H, t, J=7.8 Hz), 7.38(1H, dd, J=8.1, 1.2 Hz), 7.44(1H, d, J=7.5Hz), 7.69(1H, s), 8.13(3H, s), 11.88(1H, s).

Example 257 Preparation of the Compound of Compound No. 257

Bromine (14.4 μL, 0.28 mmol) and iron powder 1.7 mg, 0.03 mmol) wereadded to a solution ofN-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-3-isopropylbenzamide(Compound No. 256; 100 mg, 0.26 mmol) in carbon tetrachloride (5 mL)under argon atmosphere, and the mixture was stirred at room temperaturefor 2 hours. The reaction mixture was diluted with ethyl acetate. Theethyl acetate layer was washed successively with water and brine, anddried over anhydrous magnesium sulfate. The residue obtained byevaporation of the solvent under reduced pressure was crystallized fromn-hexane/ethyl acetate to give the title compound (110 mg, 91.5%) as awhite solid.

¹H-NMR(CDCl₃): δ 1.25(6H, d, J=6.9 Hz), 3.39(1H, Hept, J=6.9 Hz),7.49-7.51(2H, m), 7.71(1H, brs), 8.11-8.14(3H, m), 11.81(1H, brs).

Example 258 Preparation of the Compound of Compound No. 258

N-Bromosuccinimide (88.2 mg, 0.50 mmol) was added to a solution ofN-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-3-methylbenzamide (CompoundNo. 58; 150 mg, 0.41 mmol) in a mixed solvent of methanol/water (3:1; 5mL), and the mixture was stirred at room temperature for 10 minutes. Thereaction mixture was diluted with ethyl acetate. The ethyl acetate layerwas washed successively with 10% aqueous sodium thiosulfate, water andbrine, and dried over anhydrous magnesium sulfate. The residue obtainedby evaporation under reduced pressure was purified by columnchromatography on silica gel (n-hexane:ethyl acetate=5:1) to give thetitle compound (167 mg, 91.5%) as a white powder.

¹H-NMR(CDCl₃): δ 2.28(3H, s), 7.47(1H, s), 7.50(1H, d, J=2.4 Hz),7.71(1H, s), 8.08(1H, brs), 8.13(2H, s), 11.71(1H, s).

Example 259 Preparation of the Compound of Compound No. 259

Using N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-3-phenylbenzamide(Compound No. 249), the same operation as the Example 258 gave the titlecompound.

Yield: 67.5%.

¹H-NMR(DMSO-d₆): δ 7.36-7.50(3H, m), 7.55-7.59(2H, m), 7.71(1H, d, J=2.1Hz), 7.93(1H, brs), 8.28(1H, d, J=2.1 Hz), 8.45(2H, s), 11.06(1H, brs),12.16(1H, brs).

Example 260 Preparation of the Compound of Compound No. 260 (1)2-Amino-4-(3,4-dichlorophenyl)thiazole

Using 3′,4′-dichloroacetophenone and thiourea as the raw materials, thesame operation as the Example 231(1) gave the title compound.

Yield: 77.8%.

¹H-NMR(DMSO-d₆): δ 7.17(2H, s), 7.24(1H, s), 7.62(1H, d, J=8.4 Hz),7.78(1H, dd, J=8.7, 2.7 Hz), 8.22(1H, d, J=2.4 Hz).

(2) 5-Chloro-2-hydroxy-N-[4-(3,4-dichlorophenyl)thiazol-2-yl]benzamide(Compound No. 260)

Using 5-chlorosalicylic acid and 2-amino-4-(3,4-dichlorophenyl)thiazoleas the raw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 15.1%.

¹H-NMR(DMSO-d₆): δ 7.08(1H, d, J=8.7 Hz), 7.52(1H, dd, J=8.7, 2.7 Hz),7.71(1H, d, J=8.4 Hz), 7.91(1H, d, J=1.8 Hz), 7.94(1H, s), 8.18(1H, d,J=1.5 Hz), 12.09(2H, bs).

Example 261 Preparation of the Compound of Compound No. 261 (1)2-Amino-4-[4-(trifluoromethyl)phenyl]thiazole

Using 4′-(trifluoromethyl)acetophenone and thiourea as the rawmaterials, the same operation as the Example 231(1) gave the titlecompound.

Yield: 77.5%.

¹H-NMR(DMSO-d₆): δ 7.18(2H, s), 7.26(1H, s), 7.72(2H, d, J=8.4 Hz),8.00(2H, d, J=8.1 Hz).

(2)5-Chloro-2-hydroxy-N-{4-[4-(trifluoromethyl)phenyl]thiazol-2-yl}benzamide(Compound No. 261)

Using 5-chlorosalicylic acid and2-amino-4-[4-(trifluoromethyl)phenyl]thiazole as the raw materials, thesame operation as the Example 3 gave the title compound.

Yield: 16.0%.

¹H-NMR(DMSO-d₆): δ 7.09(1H, d, J=9.0 Hz), 7.53(1H, dd, J=8.7, 2.7 Hz),7.81(2H, d, J=8.4 Hz), 7.96(1H, d, J=2.4 Hz), 7.98(1H, s), 8.16(2H, d,J=8.1 Hz), 11.91(1H, bs), 12.13(1H, bs).

Example 262 Preparation of the Compound of Compound No. 262 (1) Methyl2-methoxy-4-phenylbenzoate

Dichlorobis(triphenylphosphine)palladium (29 mg, 0.04 mmol) was added toa solution of methyl 4-chloro-2-methoxybenzoate (904 mg, 4.5 mmol),phenylboronic acid (500 mg, 4.1 mmol) and cesium carbonate (2.7 g, 8.2mmol) in N,N-dimethylformamide (15 mL) under argon atmosphere, and themixture was stirred at 120° C. for 8 hours. After the reaction mixturewas cooled to room temperature, it was diluted with ethyl acetate. Theethyl acetate layer was washed successively with water and brine, anddried over anhydrous sodium sulfate. The residue obtained by evaporationof the solvent under reduced pressure was purified by columnchromatography on silica gel (n-hexane:ethyl acetate=10:1) to give thetitle compound (410 mg, 41.2%) as a colourless oil.

¹H-NMR(CDCl₃): δ 3.91(3H, s), 3.98(3H, s), 7.17(1H, d, J=1.5 Hz),7.20(1H, dd, J=8.1, 1.5 Hz), 7.31-7.50(3H, m), 7.59-7.63(2H, m),7.89(1H, d, J=8.1 Hz).

(2) 2-Methoxy-4-phenylbenzoic acid

2N Aqueous sodium hydroxide (5 mL) was added to a solution of methyl2-methoxy-4-phenylbenzoate (410 mg, 1.69 mmol) in methanol (5 mL), andthe mixture was refluxed for 1 hour. After the reaction mixture wascooled to room temperature, the solvent was evaporated under reducedpressure. 2N hydrochloric acid was added to the obtained residue and theseparated crystal was filtered to give the title compound (371 mg,96.0%) as a crude product.

¹H-NMR(DMSO-d₆): δ 3.93(3H, s), 7.29(1H, dd, J=8.1, 1.5 Hz), 7.34(1H, d,J=1.5 Hz), 7.40-7.53(3H, m), 7.73-7.77(3H, m), 12.60(1H, s).

(3) N-[3,5-Bis(trifluoromethyl)phenyl]-2-methoxy-4-phenylbenzamide

Using 2-methoxy-4-phenylbenzoic acid and 3,5-bis(trifluoromethyl)anilineas the raw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 97.5%.

¹H-NMR(CDCl₃): δ 4.19(3H, s), 7.25(1H, m), 7.38-7.53(4H, m),7.62-7.65(3H, m), 8.12(2H, s), 8.35(1H, d, J=8.1 Hz), 10.15(1H, brs).

(4) N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-4-phenylbenzamide(Compound No. 262)

1M Boron tribromide-dichloromethane solution (0.71 mL, 0.71 mmol) wasadded to a solution ofN-[3,5-bis(trifluoromethyl)phenyl]-2-methoxy-4-phenylbenzamide (10 mg,0.24 mmol) in dichloromethane (5 mL), and the mixture was stirred atroom temperature for 1 hour. The reaction mixture was diluted with ethylacetate, washed successively with water and brine, and dried overanhydrous magnesium sulfate. The residue obtained by evaporation of thesolvent under reduced pressure was purified by column chromatography onsilica gel (n-hexane:ethyl acetate=5:1) to give the title compound (69.3mg, 71.6%) as a white powder.

¹H-NMR(DMSO-d₆): δ 7.20(1H, dd, J=8.4.1.8 Hz), 7.30(1H, d, J=1.8 Hz),7.39-7.51(3H, m), 7.60-7.64(3H, m), 7.70(1H, brs), 8.15(2H, s), 8.19(1H,brs), 11.59(1H, s).

Example 263 Preparation of the Compound of Compound No. 263 (1)2-Amino-4-(2,5-difluorophenyl)thiazole

Using 2′,5′-difluoroacetophenone and thiourea as the raw materials, thesame operation as the Example 231(1) gave the title compound.

Yield: 77.8%.

¹H-NMR(DMSO-d₆): δ 7.45(1H, d, J=2.7 Hz), 7.11-7.17(1H, m), 7.19(2H, s),7.28-7.36(1H, m), 7.65-7.71(1H, m).

(2) 5-Chloro-2-hydroxy-N-[4-(2,5-difluorophenyl)thiazol-2-yl]benzamide(Compound No. 263)

Using 5-chlorosalicylic acid and 2-amino-4-(2,5-difluorophenyl)thiazoleas the raw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 36.5%.

¹H-NMR(DMSO-d₆): δ 7.09(1H, d, J=8.7 Hz), 7.22-7.30(1H, m), 7.37(1H, m),7.53(1H, dd, J=8.7, 3.0 Hz), 7.72(1H, d, J=2.4 Hz), 7.77-7.84(1H, m),7.94(1H, d, J=3.0 Hz), 11.89(1H, bs), 12.12(1H, bs).

Example 264 Preparation of the Compound of Compound No. 264 (1)2-Amino-4-(4-methoxyphenyl)thiazole

Using 4′-methoxyacetophenone and thiourea as the raw materials, the sameoperation as the Example 231(1) gave the title compound.

Yield: 85.2%.

¹H-NMR(DMSO-d₆): δ 3.76(3H, s), 6.82(1H, s), 6.92(2H, d, J=9.0 Hz),7.01(2H, s), 7.72(2H, d, J=8.7 Hz).

(2) 5-Chloro-2-hydroxy-N-[4-(4-methoxyphenyl)thiazol-2-yl]benzamide(Compound No. 264)

Using 5-chlorosalicylic acid and 2-amino-4-(4-methoxyphenyl)thiazole asthe raw materials, the same operation as the Example 3 gave the titlecompound.

Yield: 16.4%.

¹H-NMR(DMSO-d₆): δ 3.80(3H, s), 7.01(2H, d, J=9.0 Hz), 7.07(1H, d, J=8.7Hz), 7.50-7.55(2H, m), 7.86(2H, d, J=9.0 Hz), 7.96(1H, d, J=2.7 Hz),11.90(1H, bs), 12.04(1H, bs).

Example 265 Preparation of the Compound of Compound No. 265 (1)2-Amino-4-[3-(trifluoromethyl)phenyl]thiazole

Using 3′-(trifluoromethyl)acetophenone and thiourea as the rawmaterials, the same operation as the Example 231(1) gave the titlecompound.

Yield: 94.1%.

¹H-NMR(DMSO-d₆): δ 7.19(2H, s), 7.27(1H, s), 7.61(2H, dd, J=3.9, 1.5Hz), 8.07-8.13(2H, m).

(2)5-Chloro-2-hydroxy-N-{4-[3-(trifluoromethyl)phenyl]thiazol-2-yl}benzamide(Compound No. 265)

Using 5-chlorosalicylic acid and2-amino-4-[3-(trifluoromethyl)phenyl]thiazole as the raw materials, thesame operation as the Example 3 gave the title compound.

Yield: 31.0%.

¹H-NMR(DMSO-d₆): δ 7.13(1H, d, J=8.7 Hz), 7.53(1H, dd, J=9.0, 2.7 Hz),7.70(1H, d, J=2.4 Hz), 7.71(1H, d, J=1.2 Hz), 7.95(1H, d, J=2.7 Hz),8.00(1H, s), 8.24-8.27(2H, m), 12.16(2H, bs).

Example 266 Preparation of the Compound of Compound No. 266 (1)2-Amino-4-(2,3,4,5,6-pentafluorophenyl)thiazole

Using 2′,3′, 4′,5′,6′-pentafluoroacetophenone and thiourea as the rawmaterials, the same operation as the Example 231(1) gave the titlecompound.

Yield: 86.7%.

¹H-NMR(CDCl₃): δ 5.19(2H, s), 6.83(1H, s).

(2)5-Chloro-2-hydroxy-N-[4-(2,3,4,5,6-pentafluorophenyl)thiazol-2-yl]benzamide(Compound No. 266)

Using 5-chlorosalicylic acid and2-amino-4-(2,3,4,5,6-pentafluorophenyl)thiazole as the raw materials,the same operation as the Example 3 gave the title compound.

Yield: 23.8%.

¹H-NMR(DMSO-d₆): δ 7.08(1H, d, J=8.7 Hz), 7.53(1H, dd, J=8.7, 2.7 Hz),7.73(1H, s), 7.93(1H, d, J=2.7 Hz), 11.85(1H, bs), 12.15(1H, bs).

Example 267 Preparation of the Compound of Compound No. 267

Using 5-chlorosalicylic acid and 2-amino-4-methylbenzophenone as the rawmaterials, the same operation as the Example 3 gave the title compound.

Yield: 8.7%.

¹H-NMR(CDCl₃): δ 2.50(3H, s), 6.98(1H, d, J=8.3 Hz), 6.99(1H, d, J=7.3Hz), 7.39(1H, dd, J=2.0, 8.6 Hz), 7.48-7.64(4H, m), 7.72(2H, d, J=7.6Hz), 7.83(1H, d, J=2.3 Hz), 8.57(1H, s), 12.18(1H, s), 12.34(1H, br.s).

Example 268 Preparation of the Compound of Compound No. 268

Iron (3 mg, 0.05 mmol) and bromine (129 μl, 2.5 mmol) were added to asolution of 2-hydroxy-N-[2,5-bis(trifluoromethyl)phenyl]benzamide(Compound No. 254; 175 mg, 0.5 mmol) in carbon tetrachloride (5 mL), andthe mixture was stirred at 50° C. for 12 hours. After the reactionmixture was cooled to room temperature, it was washed with saturatedaqueous sodium hydrogen carbonate, water and brine, and dried overanhydrous magnesium sulfate. The residue obtained by evaporation of thesolvent under reduced pressure was purified by column chromatography onsilica gel (n-hexane:ethyl acetate=2:1) to give the title compound(184.2 mg, 72.7%) as a white

¹H-NMR(DMSO-d₆): δ 7.92-7.98(1H, m), 8.06(1H, d,J=2.1 Hz), 8.09(1H, d,J=8.4 Hz), 8.22(1H, d, J=2.1 Hz), 8.27-8.32(1H, m), 11.31(1H, s).

Text Example 1 Inhibitory Test Against Cancer Cell Proliferation (1)

Cancer cells (Jurkat: Human T-cell leukemia, MIA PACA-2: Humanpancreatic cancer, RD: Human rhabdomyoma, HepG2: Human liver cancer)were cultured for 3 days in the presence or absence of a test compoundusing RPMI1640 medium containing 10% bovine fetal serum or Dalbecco'sModified Eagle's Medium containing 10% FBS. The number of living cellswas counted by MTS method, and amounts of cell proliferation werecompared and inhibitory ratios were measured. In the table below, 50%inhibitory concentrations against the proliferation of each cancer cellare shown. Compound IC₅₀(μM) Number Jurkat MIA PaCa-2 RD HepG2 4 0.740.65 1.03 0.69 6 0.38 0.60 0.74 0.61 11 1.21 0.78 1.96 1.82 19 2.06 1.752.84 2.63 23 1.99 1.53 2.01 1.96 27 1.20 1.19 1.26 1.96 29 1.64 1.552.20 1.84 51 1.28 1.03 1.31 1.88 90 0.48 0.51 0.49 1.97 93 1.43 0.811.87 1.99 140 2.43 1.42 3.19 2.57 199 0.44 0.46 0.57 1.26 201 0.57 0.490.59 1.37 205 1.89 1.45 1.94 3.50 207 1.64 1.26 1.52 1.76

Test Example 2 Inhibitory Test Against Cancer Cell Proliferation (2)

Cancer cells (B16 melanoma, HT-1080 fibrosarcoma, NB-1 neuroblastoma,HMC-1-8 breast cancer) were cultured in the presence of a test compound(0.1, 1.0, 5.0, 10 μM) or in the absence of the test compound usingModified Eagle's Medium containing 5% bovine fetal serum without phenolred or RPM11640 medium containing 5% bovine fetal serum. After 24, 48and 72 hours, the number of living cells was counted by the MTT method.The results of Compound No. 4 obtained by the above method are shown inFIGS. 1 to 4.

Test Example 3 Metastasis Inhibitory Test Using B16 Mouse Bearing B16Melanoma

B16 melanoma cells (5×10⁵ cells/mouse) were inoculated from a tail veinof a B6 mouse of the same kind by intravenous injection, and a testsubstance was administered once a day for 5 weeks from the day of theinoculation by intraperitoneal injection. Then, the test animal wassacrificed and the lungs were removed. The number of colonies ofmelanoma in the lungs was compared with that in the control (testsubstance administered at 0 mg/kg). The results are shown below.Compound Survival Ratio Number Dose(mg/kg) after 5 weeks(%) ColonyFormation − 0 50 − 4 30 100 ++±: Same as control;+: Inhibited;++: Remarkably inhibited;+++: No Formation

Test Example 4 Toxicity Test By Continuous Administration

A test compound (30 mg/kg) was administered intraperitoneally to a6-week-old male SD rat once a day for 4 weeks. After the administrationwas completed, urinalysis, hematoscopy, and biochemical examination ofblood were carried out, and as a result, no findings that indicatedtoxicity were observed. These results indicate that, at an effectivedose to exhibit anticancer action, the medicament of the presentinvention has no toxic action that relate to side effects observed withexisting anticancer agents such as hepatic disorder, renal disorder, andmyelosuppression.

Test Example 5 Anticancer Effects on Tumors

Human breast cancer cells engrafted in a nude mouse and sufficientlyproliferated were isolated and cut in 5 mm squares. The cells weretransplanted in the back of 4-weel-old female nude mice under etheranesthesia. Two weeks after the transplantation of the tumor, a testcompound was administered intraperitoneally once a day. The day beforethe start of the administration of the test compound was regarded as 0days (day 0), and each volume of the tumor (tumor volume; unit: mm³)after 7 days, 14 days, 21 days, and 28 days was measured. The resultswhen 5 mg/kg or 10 mg/kg of Compound No. 4 was administered as the testcompound and those of the control (test compound dose: 0 mg/kg) areshown in FIG. 5. In FIG. 5, “control” shows the result when 0 mg/kg ofthe test compound was administered, and “Compound 4” shows the resultwhen Compound No. 4 was administered.

Test Example 6 Inhibitory Test Against Cancer Cell Proliferation (3)

Similar operations to Test Example 1 were carried out using cancer cells(HepG2: human liver cancer, A⁵⁴⁹: human lung cancer, MIA PACA-2: humanpancreatic cancer). In the table below, 50% inhibitory concentrationsagainst proliferation of each cancer cell are shown. Compound IC₅₀(μM)Number HepG2 A549 MIA PaCa-2 4 0.72 4.03 0.82 75 0.79 2.06 0.95 189 1.306.47 2.15 192 11.02 23.91 9.42 199 0.59 5.15 0.56 205 4.23 >10 >10 2133.41 7.43 4.69 215 4.98 8.31 2.76

INDUSTRIAL APPLICABILITY

The medicament of the present invention has superior anticancer actionsand reduced side effects and toxicity. Therefore, the medicament isuseful as an agent for preventive and/or therapeutic treatment ofcancers.

1. A medicament for the prevention and/or treatment of cancers whichcomprises as an active ingredient a substance selected from the groupconsisting of a compound represented by the following general formula(I) and a pharmacologically acceptable salt thereof, and a hydratethereof and a solvate thereof:

wherein A represents hydrogen atom or acetyl group, E represents a2,5-di-substituted or a 3,5-di-substituted phenyl group, or a monocyclicor a fused polycyclic heteroaryl group which may be substituted,provided that the compound wherein said heteroaryl group is (1) a fusedpolycyclic heteroaryl group wherein the ring which binds directly to—CONH— group in the formula (I) is a benzene ring, (2) unsubstitutedthiazol-2-yl group, or (3) unsubstituted benzothiazol-2-yl group isexcluded, ring Z represents an arene which may have one or moresubstituents in addition to the group represented by formula —O-Awherein A has the same meaning as that defined above and the grouprepresented by formula —CONH-E wherein E has the same meaning as thatdefined above, or a heteroarene which may have one or more substituentsin addition to the group represented by formula —O-A wherein A has thesame meaning as that defined above and the group represented by formula—CONH-E wherein E has the same meaning as that defined above.
 2. Themedicament according to claim 1, wherein A is a hydrogen atom.
 3. Themedicament according to claim 1, wherein ring Z is a C₆ to C₁₀ arenewhich may have one or more substituents in addition to the grouprepresented by formula —O-A wherein A has the same meaning as thatdefined in the general formula (I) and the group represented by formula—CONH-E wherein E has the same meaning as that defined in the generalformula (I), or a 5 to 10-membered heteroarene which may have one ormore substituents in addition to the group represented by formula —O-Awherein A has the same meaning as that defined in the general formula(I) and the group represented by formula —CONH-E wherein E has the samemeaning as that defined in the general formula (I).
 4. The medicamentaccording to claim 3, wherein ring Z is a benzene ring which may haveone or more substituents in addition to the group represented by formula—O-A wherein A has the same meaning as that defined in the generalformula (I) and the group represented by formula —CONH-E wherein E hasthe same meaning as that defined in the general formula (I), or anaphthalene ring which may have one or more substituents in addition tothe group represented by formula —O-A wherein A has the same meaning asthat defined in the general formula (I) and the group represented byformula —CONH-E wherein E has the same meaning as that defined in thegeneral formula (I).
 5. The medicament according to claim 4, whereinring Z is a benzene ring which is substituted with halogen atom(s) inaddition to the group represented by formula —O-A wherein A has the samemeaning as that defined in the general formula (I) and the grouprepresented by formula —CONH-E wherein E has the same meaning as thatdefined in the general formula (I).
 6. The medicament according to claim4, wherein ring Z is a naphthalene ring.
 7. The medicament according toclaim 1, wherein E is a 2,5-di-substituted phenyl group or a3,5-di-substituted phenyl group.
 8. The medicament according to claim 7,wherein E is a 2,5-di-substituted phenyl group wherein at least one ofthe said substituents is trifluoromethyl group, or a 3,5-di-substitutedphenyl group wherein at least one of the said substituents istrifluoromethyl group.
 9. The medicament according to claim 8, wherein Eis 3,5-bis(trifluoromethyl)phenyl group.
 10. The medicament according toclaim 1, wherein E is a monocyclic or a fused polycyclic heteroarylgroup which may be substituted, provided that the compound wherein saidheteroaryl group is (1) a fused polycyclic heteroaryl group wherein thering which binds directly to —CONH— group in the formula (I) is abenzene ring, (2) unsubstituted thiazol-2-yl group, or (3) unsubstitutedbenzothiazol-2-yl group is excluded.
 11. The medicament according toclaim 10, wherein E is a 5-membered monocyclic heteroaryl group whichmay be substituted, provided that the compounds wherein said heteroarylgroup is unsubstituted thiazol-2-yl group are excluded.